Pub Date : 2024-08-08DOI: 10.3389/frabi.2024.1375980
Dima Al Jammal, Julia Bachir, Jihane A. Moussa, Jamal Wadi Al Ramahi
To evaluate the in vitro antimicrobial susceptibilities of Gram-positive and Gram-negative isolates from patients in Jordan between 2010 and 2021, through the Antimicrobial Testing Leadership and Surveillance (ATLAS) programme.Medical centres in Jordan collected bacterial isolates from hospitalised patients with defined infection sources between 2010 and 2021 (no isolates collected in 2014). Antimicrobial susceptibility was interpreted using CLSI standards. FDA-approved breakpoints were applied for tigecycline. The identification of β-lactamase genes was performed for a proportion of isolates using multiplex PCR assays.More than 92% of Acinetobacter baumannii collected were multidrug-resistant (MDR) and/or carbapenem-resistant (CR), and > 50% susceptibility was reported only to minocycline (62.2% among both MDR and CR isolates). Rates of MDR and CR Pseudomonas aeruginosa were 14.3% and 20.5%, respectively, and among all P. aeruginosa collected from adults, susceptibility to ceftazidime/avibactam was 95.3% and to ceftolozane/tazobactam was 88.4%. For Escherichia coli from adults and MDR E. coli, susceptibility to ceftazidime/avibactam, ceftolozane/tazobactam, imipenem, meropenem and meropenem/vaborbactam was 92.1%–98.7%. Susceptibility to tigecycline was > 94% among Klebsiella pneumoniae from adult, paediatric, and ICU patients (all ages). CTX-M-15 was the most frequently identified β-lactamase gene among E. coli and K. pneumoniae. Susceptibility to most antimicrobial agents was < 50% among K. pneumoniae carrying CTX-M-15, CTX-M-9-type, NDM-5, and/or OXA-48 β-lactamase genes. All S. aureus collected were susceptible to teicoplanin, vancomycin, daptomycin, linezolid and tigecycline, with 96.1% of S. aureus from adults were susceptible to ceftaroline. Overall, 58.8% of Staphylococcus aureus were MRSA.This study provides valuable information regarding antimicrobial susceptibility in Jordan between 2010 and 2021. Continued monitoring of in vitro antimicrobial susceptibility is critical in the fight against antimicrobial resistance.
{"title":"In vitro antimicrobial susceptibility of clinical isolates from adult and paediatric patients in Jordan: Antimicrobial Testing Leadership and Surveillance (ATLAS) 2010–2021","authors":"Dima Al Jammal, Julia Bachir, Jihane A. Moussa, Jamal Wadi Al Ramahi","doi":"10.3389/frabi.2024.1375980","DOIUrl":"https://doi.org/10.3389/frabi.2024.1375980","url":null,"abstract":"To evaluate the in vitro antimicrobial susceptibilities of Gram-positive and Gram-negative isolates from patients in Jordan between 2010 and 2021, through the Antimicrobial Testing Leadership and Surveillance (ATLAS) programme.Medical centres in Jordan collected bacterial isolates from hospitalised patients with defined infection sources between 2010 and 2021 (no isolates collected in 2014). Antimicrobial susceptibility was interpreted using CLSI standards. FDA-approved breakpoints were applied for tigecycline. The identification of β-lactamase genes was performed for a proportion of isolates using multiplex PCR assays.More than 92% of Acinetobacter baumannii collected were multidrug-resistant (MDR) and/or carbapenem-resistant (CR), and > 50% susceptibility was reported only to minocycline (62.2% among both MDR and CR isolates). Rates of MDR and CR Pseudomonas aeruginosa were 14.3% and 20.5%, respectively, and among all P. aeruginosa collected from adults, susceptibility to ceftazidime/avibactam was 95.3% and to ceftolozane/tazobactam was 88.4%. For Escherichia coli from adults and MDR E. coli, susceptibility to ceftazidime/avibactam, ceftolozane/tazobactam, imipenem, meropenem and meropenem/vaborbactam was 92.1%–98.7%. Susceptibility to tigecycline was > 94% among Klebsiella pneumoniae from adult, paediatric, and ICU patients (all ages). CTX-M-15 was the most frequently identified β-lactamase gene among E. coli and K. pneumoniae. Susceptibility to most antimicrobial agents was < 50% among K. pneumoniae carrying CTX-M-15, CTX-M-9-type, NDM-5, and/or OXA-48 β-lactamase genes. All S. aureus collected were susceptible to teicoplanin, vancomycin, daptomycin, linezolid and tigecycline, with 96.1% of S. aureus from adults were susceptible to ceftaroline. Overall, 58.8% of Staphylococcus aureus were MRSA.This study provides valuable information regarding antimicrobial susceptibility in Jordan between 2010 and 2021. Continued monitoring of in vitro antimicrobial susceptibility is critical in the fight against antimicrobial resistance.","PeriodicalId":73065,"journal":{"name":"Frontiers in antibiotics","volume":"30 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141927610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-07DOI: 10.3389/frabi.2024.1437802
I. Pala-Ozkok, Tugce Katipoglu-Yazan
{"title":"Editorial: Antibiotics in engineered and natural environments: occurrence, fate, kinetic and microbial impact","authors":"I. Pala-Ozkok, Tugce Katipoglu-Yazan","doi":"10.3389/frabi.2024.1437802","DOIUrl":"https://doi.org/10.3389/frabi.2024.1437802","url":null,"abstract":"","PeriodicalId":73065,"journal":{"name":"Frontiers in antibiotics","volume":" 20","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141372908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-21DOI: 10.3389/frabi.2024.1388039
Amy D. Thompson, D. Neville, Laura Chapman, F. Balamuth, Meagan M. Ladell, A. Kharbanda, Rachael K. Aresco, L. Nigrovic
The 2018 Infectious Disease Committee of the American Academy of Pediatrics stated that up to 3 weeks or less of doxycycline is safe in children of all ages. Our goal was to examine trends in doxycycline treatment for children with Lyme disease.We assembled a prospective cohort of children aged 1 to 21 years with Lyme disease who presented to one of eight participating Pedi Lyme Net centers between 2015 and 2023. We defined a Lyme disease case with an erythema migrans (EM) lesion or positive two-tier Lyme disease serology categorized by stage: early-localized (single EM lesion), early-disseminated (multiple EM lesions, cranial neuropathy, meningitis, and carditis), and late (arthritis). We compared doxycycline treatment by age and disease stage and used logistic regression to examine treatment trends.Of the 1,154 children with Lyme disease, 94 (8.1%) had early-localized, 449 (38.9%) had early-disseminated, and 611 (53.0%) had late disease. Doxycycline treatment was more common for older children (83.3% ≥ 8 years vs. 47.1% < 8 years; p < 0.001) and with early-disseminated disease (77.2% early-disseminated vs. 52.1% early-localized or 62.1% late; p < 0.001). For children under 8 years, doxycycline use increased over the study period (6.9% 2015 to 67.9% 2023; odds ratio by year, 1.45; 95% confidence interval, 1.34–1.58).Young children with Lyme disease are frequently treated with doxycycline. Prospective studies are needed to confirm the safety and efficacy of doxycycline in children younger than 8 years, especially for those receiving courses longer than 3 weeks.
{"title":"Increased usage of doxycycline for young children with Lyme disease","authors":"Amy D. Thompson, D. Neville, Laura Chapman, F. Balamuth, Meagan M. Ladell, A. Kharbanda, Rachael K. Aresco, L. Nigrovic","doi":"10.3389/frabi.2024.1388039","DOIUrl":"https://doi.org/10.3389/frabi.2024.1388039","url":null,"abstract":"The 2018 Infectious Disease Committee of the American Academy of Pediatrics stated that up to 3 weeks or less of doxycycline is safe in children of all ages. Our goal was to examine trends in doxycycline treatment for children with Lyme disease.We assembled a prospective cohort of children aged 1 to 21 years with Lyme disease who presented to one of eight participating Pedi Lyme Net centers between 2015 and 2023. We defined a Lyme disease case with an erythema migrans (EM) lesion or positive two-tier Lyme disease serology categorized by stage: early-localized (single EM lesion), early-disseminated (multiple EM lesions, cranial neuropathy, meningitis, and carditis), and late (arthritis). We compared doxycycline treatment by age and disease stage and used logistic regression to examine treatment trends.Of the 1,154 children with Lyme disease, 94 (8.1%) had early-localized, 449 (38.9%) had early-disseminated, and 611 (53.0%) had late disease. Doxycycline treatment was more common for older children (83.3% ≥ 8 years vs. 47.1% < 8 years; p < 0.001) and with early-disseminated disease (77.2% early-disseminated vs. 52.1% early-localized or 62.1% late; p < 0.001). For children under 8 years, doxycycline use increased over the study period (6.9% 2015 to 67.9% 2023; odds ratio by year, 1.45; 95% confidence interval, 1.34–1.58).Young children with Lyme disease are frequently treated with doxycycline. Prospective studies are needed to confirm the safety and efficacy of doxycycline in children younger than 8 years, especially for those receiving courses longer than 3 weeks.","PeriodicalId":73065,"journal":{"name":"Frontiers in antibiotics","volume":"42 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141113688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-20DOI: 10.3389/frabi.2024.1395425
Katrina J Holly, Arti Kataria, Daniel P. Flaherty, Ashley M Groshong
Recent reports from the Centers for Disease Control and Prevention approximate 500,000 cases of Lyme disease in the United States yearly, a significant economic burden on the healthcare system. The standard treatment for Lyme disease includes broad-spectrum antibiotics, which may be administered for extensive periods of time and result in significant impacts to the patient. Recently, we demonstrated that Borrelia burgdorferi, the causative agent of Lyme disease, is uniquely dependent upon peptide acquisition via an oligopeptide transport (Opp) system. This dependence appears unique to the spirochete; thus, the Opp system may constitute a novel and specific target for the inhibition of B. burgdorferi. For proof of concept, we conducted a pilot screen to determine if the Opp system constitutes a viable inhibitor target. OppA2 was utilized as our target protein as it is the most prolific peptide-binding protein throughout the enzootic cycle. We validated a thermal shift assay (TSA) to detect ligand binding against OppA2 and performed a high-throughput screen of 2,240 molecules from a diversity set library. The TSA results identified eight compounds (C1–8) demonstrating potential binding to OppA2, and growth assays identified C2 and C7 as inhibitors of B. burgdorferi growth. We confirmed by TSA that these two compounds interact with additional B. burgdorferi OppAs, potentially resulting in a cumulative inhibitory effect. Additionally, we showed that these compounds have no effect on Escherichia coli, a bacterium that encodes a dispensable Opp system which serves only as an ancillary nutrient transporter. These data demonstrate that the Opp system of B. burgdorferi acts as a viable drug target, with the potential for targeting multiple OppAs with a single compound. Moreover, the lack of inhibition against E. coli suggests that selective targeting of B. burgdorferi via the Opp system may be possible.
美国疾病控制与预防中心最近的报告显示，美国每年约有 50 万例莱姆病病例，给医疗系统造成了巨大的经济负担。莱姆病的标准治疗方法包括广谱抗生素，这种抗生素可能需要长期使用，对患者造成严重影响。最近，我们证实，莱姆病的致病菌鲍瑞氏菌（Borrelia burgdorferi）独特地依赖于通过寡肽转运（Opp）系统获取肽。这种依赖性似乎是螺旋体所独有的；因此，Opp 系统可能是抑制 B. burgdorferi 的一个新的特异性靶点。为了证明这一概念，我们进行了一次试验性筛选，以确定 Opp 系统是否是一个可行的抑制剂靶点。我们将 OppA2 作为目标蛋白，因为它是整个侵袭周期中最多的肽结合蛋白。我们验证了热转移检测法（TSA）来检测配体与 OppA2 的结合，并从多样性集库中对 2240 个分子进行了高通量筛选。TSA 结果确定了八种化合物（C1-8）与 OppA2 有潜在的结合力，生长试验确定了 C2 和 C7 是 B. burgdorferi 生长的抑制剂。我们通过 TSA 证实，这两种化合物与更多的 B. burgdorferi OppAs 相互作用，可能产生累积抑制作用。此外，我们还发现这两种化合物对大肠杆菌没有影响，大肠杆菌编码了一种可有可无的 Opp 系统，该系统只是一种辅助性的营养物质转运体。这些数据表明，布氏菌的Opp系统是一个可行的药物靶点，有可能用一种化合物靶向多种OppAs。此外，对大肠杆菌没有抑制作用表明，通过 Opp 系统选择性地靶向布氏菌是可能的。
{"title":"Unguarded liabilities: Borrelia burgdorferi’s complex amino acid dependence exposes unique avenues of inhibition","authors":"Katrina J Holly, Arti Kataria, Daniel P. Flaherty, Ashley M Groshong","doi":"10.3389/frabi.2024.1395425","DOIUrl":"https://doi.org/10.3389/frabi.2024.1395425","url":null,"abstract":"Recent reports from the Centers for Disease Control and Prevention approximate 500,000 cases of Lyme disease in the United States yearly, a significant economic burden on the healthcare system. The standard treatment for Lyme disease includes broad-spectrum antibiotics, which may be administered for extensive periods of time and result in significant impacts to the patient. Recently, we demonstrated that Borrelia burgdorferi, the causative agent of Lyme disease, is uniquely dependent upon peptide acquisition via an oligopeptide transport (Opp) system. This dependence appears unique to the spirochete; thus, the Opp system may constitute a novel and specific target for the inhibition of B. burgdorferi. For proof of concept, we conducted a pilot screen to determine if the Opp system constitutes a viable inhibitor target. OppA2 was utilized as our target protein as it is the most prolific peptide-binding protein throughout the enzootic cycle. We validated a thermal shift assay (TSA) to detect ligand binding against OppA2 and performed a high-throughput screen of 2,240 molecules from a diversity set library. The TSA results identified eight compounds (C1–8) demonstrating potential binding to OppA2, and growth assays identified C2 and C7 as inhibitors of B. burgdorferi growth. We confirmed by TSA that these two compounds interact with additional B. burgdorferi OppAs, potentially resulting in a cumulative inhibitory effect. Additionally, we showed that these compounds have no effect on Escherichia coli, a bacterium that encodes a dispensable Opp system which serves only as an ancillary nutrient transporter. These data demonstrate that the Opp system of B. burgdorferi acts as a viable drug target, with the potential for targeting multiple OppAs with a single compound. Moreover, the lack of inhibition against E. coli suggests that selective targeting of B. burgdorferi via the Opp system may be possible.","PeriodicalId":73065,"journal":{"name":"Frontiers in antibiotics","volume":"78 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141121238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-16DOI: 10.3389/frabi.2024.1351725
Ashesh Basnet, Agnes Kilonzo-Nthenge
The increase of antimicrobial resistance (AMR) in zoonotic pathogens poses a substantial threat to both animal production and human health. Although large-scale animal farms are acknowledged as major reservoirs for AMR, there is a notable knowledge gap concerning AMR in small-scale farms. This study seeks to address this gap by collecting and analyzing 137 fecal samples from goat and sheep farms in Tennessee and Georgia.Bacteria were identified using culture-dependent methods and polymerase chain reaction (PCR), and antimicrobial susceptibility testing (AST) was performed using the Kirby-Bauer Disk Diffusion method.The prevalence of E. coli (94.9%) in goats and sheep significantly exceeded (p < 0.05) that of S. aureus (81.0%), Shigella (35.0%), S. saprophyticus, and Salmonella (3.0%). Salmonella occurrence in goat feces (2.2%) was higher than in sheep (0.8%). Notably, 27% of goats and 8% of sheep tested positive for Shigella spp., while 60% of goats and 21% of sheep tested positive for S. aureus. Antibiotic resistance was observed primarily against ampicillin (79.4%), vancomycin (65.1%), and gentamycin (63.6%), significantly surpassing (p < 0.05) resistance to tetracycline (41.6%) and imipenem (21.8%). The penicillin (79.4%), glycopeptide (65.1%), and aminoglycoside (63.6%) antibiotic classes displayed significantly higher (p < 0.05) resistance compared to tetracyclines (45.7%) and carbapenem (21.8%). Our findings suggest that goats and sheep feces may serve as source for multidrug-resistant bacteria, raising concerns about the potential introduction of their fecal matter into soil, water, and eventually to the food chain. This highlights the need for proactive measures to address and mitigate AMR in goats and sheep within small-scale farms.
人畜共患病原体的抗菌药耐药性（AMR）的增加对动物生产和人类健康都构成了巨大威胁。尽管大规模动物养殖场被公认为是 AMR 的主要贮藏库，但有关小规模养殖场 AMR 的知识却存在明显空白。本研究收集并分析了田纳西州和佐治亚州山羊和绵羊养殖场的 137 份粪便样本，试图填补这一空白。细菌的鉴定采用依赖培养的方法和聚合酶链式反应 (PCR)，抗菌药物敏感性测试 (AST) 采用柯比鲍尔盘扩散法。山羊和绵羊中大肠杆菌的感染率（94.9%）明显高于金黄色葡萄球菌（81.0%）、志贺氏菌（35.0%）、沙门氏菌和沙门氏菌（3.0%）（P < 0.05）。山羊粪便中的沙门氏菌（2.2%）高于绵羊（0.8%）。值得注意的是，27% 的山羊和 8% 的绵羊对志贺氏菌属检测呈阳性，而 60% 的山羊和 21% 的绵羊对金黄色葡萄球菌检测呈阳性。抗生素耐药性主要针对氨苄西林（79.4%）、万古霉素（65.1%）和庆大霉素（63.6%），大大超过了四环素（41.6%）和亚胺培南（21.8%）（p < 0.05）。与四环素类（45.7%）和碳青霉烯类（21.8%）相比，青霉素类（79.4%）、糖肽类（65.1%）和氨基糖苷类（63.6%）抗生素的耐药性明显更高（p < 0.05）。我们的研究结果表明，山羊和绵羊的粪便可能是耐多药细菌的来源，这引起了人们对山羊和绵羊粪便可能进入土壤、水体并最终进入食物链的担忧。这突出表明，有必要采取积极措施来解决和减轻小型农场中山羊和绵羊的 AMR 问题。
{"title":"Antibiogram profiles of pathogenic and commensal bacteria in goat and sheep feces on smallholder farm","authors":"Ashesh Basnet, Agnes Kilonzo-Nthenge","doi":"10.3389/frabi.2024.1351725","DOIUrl":"https://doi.org/10.3389/frabi.2024.1351725","url":null,"abstract":"The increase of antimicrobial resistance (AMR) in zoonotic pathogens poses a substantial threat to both animal production and human health. Although large-scale animal farms are acknowledged as major reservoirs for AMR, there is a notable knowledge gap concerning AMR in small-scale farms. This study seeks to address this gap by collecting and analyzing 137 fecal samples from goat and sheep farms in Tennessee and Georgia.Bacteria were identified using culture-dependent methods and polymerase chain reaction (PCR), and antimicrobial susceptibility testing (AST) was performed using the Kirby-Bauer Disk Diffusion method.The prevalence of E. coli (94.9%) in goats and sheep significantly exceeded (p < 0.05) that of S. aureus (81.0%), Shigella (35.0%), S. saprophyticus, and Salmonella (3.0%). Salmonella occurrence in goat feces (2.2%) was higher than in sheep (0.8%). Notably, 27% of goats and 8% of sheep tested positive for Shigella spp., while 60% of goats and 21% of sheep tested positive for S. aureus. Antibiotic resistance was observed primarily against ampicillin (79.4%), vancomycin (65.1%), and gentamycin (63.6%), significantly surpassing (p < 0.05) resistance to tetracycline (41.6%) and imipenem (21.8%). The penicillin (79.4%), glycopeptide (65.1%), and aminoglycoside (63.6%) antibiotic classes displayed significantly higher (p < 0.05) resistance compared to tetracyclines (45.7%) and carbapenem (21.8%). Our findings suggest that goats and sheep feces may serve as source for multidrug-resistant bacteria, raising concerns about the potential introduction of their fecal matter into soil, water, and eventually to the food chain. This highlights the need for proactive measures to address and mitigate AMR in goats and sheep within small-scale farms.","PeriodicalId":73065,"journal":{"name":"Frontiers in antibiotics","volume":"15 23","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140966705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-08DOI: 10.3389/frabi.2024.1362516
Mousumi Shyam, Abhishek Thakur, Caroline Velez, Chris Daniel, Orlando Acevedo, S. Bhakta, Venkatesan Jayaprakash
In response to continued public health emergency of antimicrobial resistance (AMR), a significant key strategy is the discovery of novel mycobacterial efflux-pump inhibitors (EPIs) as potential adjuvants in combination drug therapy. Interest in identifying new chemotypes which could potentially synergize with the existing antibiotics and can be deployed as part of a combination therapy. This strategy could delay the emergence of resistance to existing antibiotics and increase their efficacy against resistant strains of mycobacterial species. In recent decades, notable approaches have been accounted for EPI development and have resulted in the discovery of several EPIs including SQ109 and AU1235. In context, to accelerate newer EPIs with novel mode of action here we have discussed mycobactin analogues and highlighted in silico binding orientation with siderophore efflux-pump proteins MmpL4/5.3-(2-hydroxyphenyl)-5-(aryl)-pyrazoline series was investigated for whole-cell efflux-pump inhibitory activity against Mycobacterium smegmatis and Mycobacterium abscessus. Machine learning and molecular dynamics were performed to construct a MmpL4/5 complex embedded in a lipid bilayer to identify the putative binding site and to predict ligand-protein binding energetics. Furthermore, the identified HIT compound was investigated in synergistic assay with bedaquiline.Compound Il, 2-(5-(4-fluorophenyl)-4,5-dihydro-1H-pyrazol-3-yl)phenol, was identified as the most potent efflux pump inhibitor against M. smegmatis in whole-cell efflux-pump investigation. Followed HIT Il employed against M. abscessus for efflux-pump inhibition investigations and notable whole-cell efflux-pump inhibitory profile has been observed. The theoretical investigations predicted compound Il to be selective towards MmpL4, with significant hydrogen bonding and π-π stacking interactions effectively blocking a critical Asp-Tyr dyad interaction network necessary for proton translocation. Compound Il with bedaquiline highlighted an additive profile against the M. abscessus pathogen.MD simulations and whole-cell assays are indicating potential development of compound Il as an adjunct to the existing therapeutic regimen against mycobacterial infections.
为应对抗菌药耐药性（AMR）这一持续的公共卫生紧急状况，一项重要的关键战略是发现新型分枝杆菌外排泵抑制剂（EPIs），作为联合药物疗法的潜在辅助剂。研究人员有兴趣发现可能与现有抗生素产生协同作用的新化学类型，并将其作为联合疗法的一部分。这种策略可以延缓现有抗生素耐药性的产生，并提高其对耐药性分枝杆菌菌株的疗效。近几十年来，用于 EPI 开发的方法引人注目，并发现了包括 SQ109 和 AU1235 在内的几种 EPI。3-(2-hydroxyphenyl)-5-(aryl)-pyrazoline 系列研究了对烟曲霉分枝杆菌和脓肿分枝杆菌的全细胞外排泵抑制活性。研究人员利用机器学习和分子动力学方法构建了嵌入脂质双分子层的 MmpL4/5 复合物，从而确定了可能的结合位点，并预测了配体与蛋白质的结合能。在全细胞外排泵研究中，化合物 Il，2-(5-(4-氟苯基)-4,5-二氢-1H-吡唑-3-基)苯酚被鉴定为对 M. smegmatis 最有效的外排泵抑制剂。在对脓肿霉菌进行外排泵抑制研究时，使用了 HIT Il，并观察到了显著的全细胞外排泵抑制特征。理论研究预测化合物 Il 对 MmpL4 具有选择性，其显著的氢键和 π-π 堆叠相互作用有效地阻断了质子转运所必需的关键 Asp-Tyr 二元相互作用网络。MD 模拟和全细胞实验表明，化合物 Il 有可能发展成为现有霉菌感染治疗方案的辅助药物。
{"title":"Mycobactin analogue interacting with siderophore efflux-pump protein: insights from molecular dynamics simulations and whole-cell assays","authors":"Mousumi Shyam, Abhishek Thakur, Caroline Velez, Chris Daniel, Orlando Acevedo, S. Bhakta, Venkatesan Jayaprakash","doi":"10.3389/frabi.2024.1362516","DOIUrl":"https://doi.org/10.3389/frabi.2024.1362516","url":null,"abstract":"In response to continued public health emergency of antimicrobial resistance (AMR), a significant key strategy is the discovery of novel mycobacterial efflux-pump inhibitors (EPIs) as potential adjuvants in combination drug therapy. Interest in identifying new chemotypes which could potentially synergize with the existing antibiotics and can be deployed as part of a combination therapy. This strategy could delay the emergence of resistance to existing antibiotics and increase their efficacy against resistant strains of mycobacterial species. In recent decades, notable approaches have been accounted for EPI development and have resulted in the discovery of several EPIs including SQ109 and AU1235. In context, to accelerate newer EPIs with novel mode of action here we have discussed mycobactin analogues and highlighted in silico binding orientation with siderophore efflux-pump proteins MmpL4/5.3-(2-hydroxyphenyl)-5-(aryl)-pyrazoline series was investigated for whole-cell efflux-pump inhibitory activity against Mycobacterium smegmatis and Mycobacterium abscessus. Machine learning and molecular dynamics were performed to construct a MmpL4/5 complex embedded in a lipid bilayer to identify the putative binding site and to predict ligand-protein binding energetics. Furthermore, the identified HIT compound was investigated in synergistic assay with bedaquiline.Compound Il, 2-(5-(4-fluorophenyl)-4,5-dihydro-1H-pyrazol-3-yl)phenol, was identified as the most potent efflux pump inhibitor against M. smegmatis in whole-cell efflux-pump investigation. Followed HIT Il employed against M. abscessus for efflux-pump inhibition investigations and notable whole-cell efflux-pump inhibitory profile has been observed. The theoretical investigations predicted compound Il to be selective towards MmpL4, with significant hydrogen bonding and π-π stacking interactions effectively blocking a critical Asp-Tyr dyad interaction network necessary for proton translocation. Compound Il with bedaquiline highlighted an additive profile against the M. abscessus pathogen.MD simulations and whole-cell assays are indicating potential development of compound Il as an adjunct to the existing therapeutic regimen against mycobacterial infections.","PeriodicalId":73065,"journal":{"name":"Frontiers in antibiotics","volume":"209 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141002048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-24DOI: 10.3389/frabi.2024.1405401
Francesco Di Gennaro
{"title":"Prescriptive appropriateness of dalbavancin in acute bacterial skin and skin structure infections in adults: an integrated approach between clinical profile, patient- and health system-related factors and focus on environmental impact","authors":"Francesco Di Gennaro","doi":"10.3389/frabi.2024.1405401","DOIUrl":"https://doi.org/10.3389/frabi.2024.1405401","url":null,"abstract":"","PeriodicalId":73065,"journal":{"name":"Frontiers in antibiotics","volume":"8 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140661663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-16DOI: 10.3389/frabi.2024.1222580
L. Veerapa-Mangroo, Harena Rasamoelina-Andriamanivo, M.I. Issack, Eric Cardinale
This study aims at determining the pattern of antibiotic consumption and resistance in Mauritius, a tropical island in the Indian Ocean.Antibiotic consumption was measured in kilograms of purchased antibiotics and also in defined daily dose (DDD) in different health institutions from 2015 to 2017. Data on antibiotic resistance was collected at the Central Health Laboratory (CHL) at Victoria Hospital and at Jeetoo Hospital Laboratory, where antibiotic sensitivity testing is done for all public health institutions. For this study, Escherichia coli, Klebsiella species, Acinetobacter species, and Pseudomonas aeruginosa isolates from blood samples of patients from 2015 to 2023 were included. The resistance rate and prevalence of multi-drug-resistant (MDR) organisms were calculated.The amount of antibiotics (in kilograms) distributed to the human sector was between 11,000 to 13,000 kg, compared to only 700 to 1,500 kg in the animal sector. The DDD per 1,000 inhabitants per day was 20.9, 22.1, and 21.7 in 2015, 2016, and 2017, respectively, with a greater consumption of WATCH and RESERVE group antibiotics in the private sector. In public health institutions, health centers in the northern region had the highest DDD per 1,000 outpatients per day for beta-lactams penicillins and quinolones. Concerning antibiotic resistance, the proportion of MDR Acinetobacter baumannii and Pseudomonas aeruginosa has increased from 58% to 74% and from 33% to 45%, respectively, from 2015 to 2023. During the same period, the proportion of E. coli and K. pneumoniae isolates sensitive to ceftriaxone decreased from 55% to 39% and from 37% to 22%, respectively, while the proportion of E. coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa isolates sensitive to meropenem decreased from 98% to 94%, 83% to 53%, 45% to 28%, and 63% to 47%, respectively.This study provides valuable insights on antibiotic consumption and resistance in the country and emphasizes the significance of adopting a One Health approach to combat antimicrobial resistance (AMR) effectively. These findings will aid policymakers in formulating targeted strategies to address the challenge of AMR and should be integrated into the National Action Plan on AMR in Mauritius.
{"title":"Epidemiology of antibiotic consumption and resistance in Mauritius","authors":"L. Veerapa-Mangroo, Harena Rasamoelina-Andriamanivo, M.I. Issack, Eric Cardinale","doi":"10.3389/frabi.2024.1222580","DOIUrl":"https://doi.org/10.3389/frabi.2024.1222580","url":null,"abstract":"This study aims at determining the pattern of antibiotic consumption and resistance in Mauritius, a tropical island in the Indian Ocean.Antibiotic consumption was measured in kilograms of purchased antibiotics and also in defined daily dose (DDD) in different health institutions from 2015 to 2017. Data on antibiotic resistance was collected at the Central Health Laboratory (CHL) at Victoria Hospital and at Jeetoo Hospital Laboratory, where antibiotic sensitivity testing is done for all public health institutions. For this study, Escherichia coli, Klebsiella species, Acinetobacter species, and Pseudomonas aeruginosa isolates from blood samples of patients from 2015 to 2023 were included. The resistance rate and prevalence of multi-drug-resistant (MDR) organisms were calculated.The amount of antibiotics (in kilograms) distributed to the human sector was between 11,000 to 13,000 kg, compared to only 700 to 1,500 kg in the animal sector. The DDD per 1,000 inhabitants per day was 20.9, 22.1, and 21.7 in 2015, 2016, and 2017, respectively, with a greater consumption of WATCH and RESERVE group antibiotics in the private sector. In public health institutions, health centers in the northern region had the highest DDD per 1,000 outpatients per day for beta-lactams penicillins and quinolones. Concerning antibiotic resistance, the proportion of MDR Acinetobacter baumannii and Pseudomonas aeruginosa has increased from 58% to 74% and from 33% to 45%, respectively, from 2015 to 2023. During the same period, the proportion of E. coli and K. pneumoniae isolates sensitive to ceftriaxone decreased from 55% to 39% and from 37% to 22%, respectively, while the proportion of E. coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa isolates sensitive to meropenem decreased from 98% to 94%, 83% to 53%, 45% to 28%, and 63% to 47%, respectively.This study provides valuable insights on antibiotic consumption and resistance in the country and emphasizes the significance of adopting a One Health approach to combat antimicrobial resistance (AMR) effectively. These findings will aid policymakers in formulating targeted strategies to address the challenge of AMR and should be integrated into the National Action Plan on AMR in Mauritius.","PeriodicalId":73065,"journal":{"name":"Frontiers in antibiotics","volume":"8 3‐4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140698559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-10DOI: 10.3389/frabi.2024.1367936
Alann Caderhoussin, D. Couvin, Gaëlle Gruel, Isaure Quétel, M. Pot, Rémy Arquet, Alexis Dereeper, J. Bambou, Antoine Talarmin, Séverine Ferdinand
This study aimed to understand the origin and to explain the maintenance of extended-spectrum β-lactamase (ESBL) Enterobacteriaceae isolated from food-producing animals in a third-generation cephalosporin (3GC)-free farm.Culture and molecular approaches were used to test molecules other than 3GC such as antibiotics (tetracycline and oxytetracycline), antiparasitics (ivermectin, flumethrin, fenbendazol, and amitraz), heavy metal [arsenic, HNO3, aluminum, HNO3, cadmium (CdSO4), zinc (ZnCl2), copper (CuSO4), iron (FeCl3), and aluminum (Al2SO4)], and antioxidant (butylated hydroxytoluene) as sources of selective pressure. Whole-genome sequencing using short read (Illumina™) and long read (Nanopore™) technologies was performed on 34 genomes. In silico gene screening and comparative analyses were used to characterize the genetic determinants of resistance, their mobility, and the genomic relatedness among isolates.Our analysis unveiled a low diversity among the animal ESBL-producing strains. Notably, E. coli ST3268 was recurrently isolated from both flies (n = 9) and cattle (n = 5). These E. coli ST3268/blaCTX-M-15/blaTEM-1B have accumulated multiple plasmids and genes, thereby representing a reservoir of resistance and virulence factors. Our findings suggest that flies could act as effective mechanical vectors for antimicrobial gene transfer and are capable of transporting resistant bacteria across different environments and to multiple hosts, facilitating the spread of pathogenic traits. A significantly higher mean minimum inhibitory concentration of oxytetracycline (841.4 ± 323.5 mg/L vs. 36.0 ± 52.6 mg/L, p = 0.0022) in ESBL E. coli than in non-ESBL E. coli and blaCTX-M-15 gene overexpression in oxytetracycline-treated vs. untreated ESBL E. coli (RQOxy = 3.593, p = 0.024) confirmed oxytetracycline as a source of selective pressure in ESBL E. coli.The occurrence of ESBL E. coli in a farm without 3GC use is probably due to an as yet undefined human origin of Enterobacteriaceae blaCTX-M-15 gene transmission to animals in close contact with cattle farm workers and the maintenance of the local ESBL E. coli reservoir by a high fly diversity and oxytetracycline selective pressure. These findings highlight the critical need for stringent vector control to mitigate antimicrobial resistance spread for preserving public health. Addressing this issue necessitates a multifaceted approach combining microbial genetics, vector ecology, and farm management practices.
{"title":"The fly route of extended-spectrum-β-lactamase-producing Enterobacteriaceae dissemination in a cattle farm: from the ecosystem to the molecular scale","authors":"Alann Caderhoussin, D. Couvin, Gaëlle Gruel, Isaure Quétel, M. Pot, Rémy Arquet, Alexis Dereeper, J. Bambou, Antoine Talarmin, Séverine Ferdinand","doi":"10.3389/frabi.2024.1367936","DOIUrl":"https://doi.org/10.3389/frabi.2024.1367936","url":null,"abstract":"This study aimed to understand the origin and to explain the maintenance of extended-spectrum β-lactamase (ESBL) Enterobacteriaceae isolated from food-producing animals in a third-generation cephalosporin (3GC)-free farm.Culture and molecular approaches were used to test molecules other than 3GC such as antibiotics (tetracycline and oxytetracycline), antiparasitics (ivermectin, flumethrin, fenbendazol, and amitraz), heavy metal [arsenic, HNO3, aluminum, HNO3, cadmium (CdSO4), zinc (ZnCl2), copper (CuSO4), iron (FeCl3), and aluminum (Al2SO4)], and antioxidant (butylated hydroxytoluene) as sources of selective pressure. Whole-genome sequencing using short read (Illumina™) and long read (Nanopore™) technologies was performed on 34 genomes. In silico gene screening and comparative analyses were used to characterize the genetic determinants of resistance, their mobility, and the genomic relatedness among isolates.Our analysis unveiled a low diversity among the animal ESBL-producing strains. Notably, E. coli ST3268 was recurrently isolated from both flies (n = 9) and cattle (n = 5). These E. coli ST3268/blaCTX-M-15/blaTEM-1B have accumulated multiple plasmids and genes, thereby representing a reservoir of resistance and virulence factors. Our findings suggest that flies could act as effective mechanical vectors for antimicrobial gene transfer and are capable of transporting resistant bacteria across different environments and to multiple hosts, facilitating the spread of pathogenic traits. A significantly higher mean minimum inhibitory concentration of oxytetracycline (841.4 ± 323.5 mg/L vs. 36.0 ± 52.6 mg/L, p = 0.0022) in ESBL E. coli than in non-ESBL E. coli and blaCTX-M-15 gene overexpression in oxytetracycline-treated vs. untreated ESBL E. coli (RQOxy = 3.593, p = 0.024) confirmed oxytetracycline as a source of selective pressure in ESBL E. coli.The occurrence of ESBL E. coli in a farm without 3GC use is probably due to an as yet undefined human origin of Enterobacteriaceae blaCTX-M-15 gene transmission to animals in close contact with cattle farm workers and the maintenance of the local ESBL E. coli reservoir by a high fly diversity and oxytetracycline selective pressure. These findings highlight the critical need for stringent vector control to mitigate antimicrobial resistance spread for preserving public health. Addressing this issue necessitates a multifaceted approach combining microbial genetics, vector ecology, and farm management practices.","PeriodicalId":73065,"journal":{"name":"Frontiers in antibiotics","volume":"2006 18","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140718487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-08DOI: 10.3389/frabi.2024.1384390
Christopher Campion, Godefroid Charbon, Peter E. Nielsen, A. Løbner‐Olesen
Initiation of chromosome replication is an essential stage of the bacterial cell cycle that is controlled by the DnaA protein. With the aim of developing novel antimicrobials, we have targeted the initiation of DNA replication, using antisense peptide nucleic acids (PNAs), directed against DnaA translation. A series of anti-DnaA PNA conjugated to lysine-rich bacterial penetrating peptides (PNA-BPPs) were designed to block DnaA translation. These anti-DnaA PNA-BPPs inhibited growth of wild-type Escherichia coli cells at low micromolar concentrations, and cells exposed to anti-DnaA PNA-BPPs exhibited characteristic hallmarks of chromosome replication inhibition. These results present one of very few compounds successfully targeting initiation of chromosome replication, an essential step in the bacterial cell cycle.
{"title":"Targeting synthesis of the Chromosome Replication Initiator Protein DnaA by antisense PNA-peptide conjugates in Escherichia coli","authors":"Christopher Campion, Godefroid Charbon, Peter E. Nielsen, A. Løbner‐Olesen","doi":"10.3389/frabi.2024.1384390","DOIUrl":"https://doi.org/10.3389/frabi.2024.1384390","url":null,"abstract":"Initiation of chromosome replication is an essential stage of the bacterial cell cycle that is controlled by the DnaA protein. With the aim of developing novel antimicrobials, we have targeted the initiation of DNA replication, using antisense peptide nucleic acids (PNAs), directed against DnaA translation. A series of anti-DnaA PNA conjugated to lysine-rich bacterial penetrating peptides (PNA-BPPs) were designed to block DnaA translation. These anti-DnaA PNA-BPPs inhibited growth of wild-type Escherichia coli cells at low micromolar concentrations, and cells exposed to anti-DnaA PNA-BPPs exhibited characteristic hallmarks of chromosome replication inhibition. These results present one of very few compounds successfully targeting initiation of chromosome replication, an essential step in the bacterial cell cycle.","PeriodicalId":73065,"journal":{"name":"Frontiers in antibiotics","volume":"30 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140729176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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