Pub Date : 2024-11-05DOI: 10.1016/j.ijantimicag.2024.107374
Mohan Ju , Min Hao , Dongfang Lin, Shuang Liu
Background
Cefiderocol is a new catecholamine-containing siderophore cephalosporin. It, however, remains unclear how cefiderocol modulates the immune response of the host.
Objectives
This study elucidated whether cefiderocol exerts immunoprotective effects in an in vitro experimental model induced with lipopolysaccharide (LPS).
Methods
Mouse macrophage RAW 264.7 cells were exposed to LPS (100 ng/mL) or LPS + cefiderocol (40 mg/L) to assess the immunomodulatory effect of cefiderocol in vitro. ELISA was performed on cell culture supernatants to estimate cytokine levels. Ferroptosis level was also quantified by detecting intracellular reactive oxygen species and iron levels through flow cytometry analysis. Malondialdehyde and glutathione (GSH) levels were estimated by ELISA. We conducted western blotting assay for evaluating key ferroptosis pathway proteins.
Results
Cefiderocol alleviated LPS-induced inflammation by reducing IL-6, TNF-α, and IL-1β production levels and enhancing the IL-10 production level. Further analysis to determine the underlying mechanism revealed that cefiderocol inhibited ferroptosis; this was confirmed by reduced reactive oxygen species, malondialdehyde, and Fe2+ ion levels; increased GSH levels; upregulated expression of solute carrier family 7 member 11, GSH peroxidase 4, nuclear factor erythroid 2-related factor 2, and ferroptosis suppressor protein 1; and downregulated expression of acyl-CoA synthetase long-chain family member 4.
Conclusions
Cefiderocol may play a key role in reducing inflammation by decreasing inflammatory cytokine release and suppressing ferroptosis.
{"title":"Cefiderocol has immunoregulative effects in LPS-induced vitro experimental model via inhibiting inflammation and ferroptosis","authors":"Mohan Ju , Min Hao , Dongfang Lin, Shuang Liu","doi":"10.1016/j.ijantimicag.2024.107374","DOIUrl":"10.1016/j.ijantimicag.2024.107374","url":null,"abstract":"<div><h3>Background</h3><div>Cefiderocol is a new catecholamine-containing siderophore cephalosporin. It, however, remains unclear how cefiderocol modulates the immune response of the host.</div></div><div><h3>Objectives</h3><div>This study elucidated whether cefiderocol exerts immunoprotective effects in an in vitro experimental model induced with lipopolysaccharide (LPS).</div></div><div><h3>Methods</h3><div>Mouse macrophage RAW 264.7 cells were exposed to LPS (100 ng/mL) or LPS + cefiderocol (40 mg/L) to assess the immunomodulatory effect of cefiderocol in vitro. ELISA was performed on cell culture supernatants to estimate cytokine levels. Ferroptosis level was also quantified by detecting intracellular reactive oxygen species and iron levels through flow cytometry analysis. Malondialdehyde and glutathione (GSH) levels were estimated by ELISA. We conducted western blotting assay for evaluating key ferroptosis pathway proteins.</div></div><div><h3>Results</h3><div>Cefiderocol alleviated LPS-induced inflammation by reducing IL-6, TNF-α, and IL-1β production levels and enhancing the IL-10 production level. Further analysis to determine the underlying mechanism revealed that cefiderocol inhibited ferroptosis; this was confirmed by reduced reactive oxygen species, malondialdehyde, and Fe<sup>2+</sup> ion levels; increased GSH levels; upregulated expression of solute carrier family 7 member 11, GSH peroxidase 4, nuclear factor erythroid 2-related factor 2, and ferroptosis suppressor protein 1; and downregulated expression of acyl-CoA synthetase long-chain family member 4.</div></div><div><h3>Conclusions</h3><div>Cefiderocol may play a key role in reducing inflammation by decreasing inflammatory cytokine release and suppressing ferroptosis.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 6","pages":"Article 107374"},"PeriodicalIF":4.9,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-31DOI: 10.1016/j.ijantimicag.2024.107375
Hao Zhang , Jun Zeng , Tingting Zhu , Tao Lin , Turun Song
Background
Tuberculosis (TB) is a major and severe opportunistic infection among solid organ transplant recipients. Chemoprophylaxis is advised for those with latent tuberculosis infection. However, the effectiveness of an isoniazid (INH) prophylactic approach based on TB risk factors remains uncertain.
Methods
This study included all living-donor kidney transplant recipients between January 2016 and December 2022. The recipients were categorized into three groups: the risk group with INH (R-INH), the risk group without INH (R-NINH), and the non-risk group (NR), based on the presence of TB risk factors and INH usage. The R-INH group received a 6-month INH prophylactic regimen to prevent post-transplant TB infection. The incidence of active TB among the groups was assessed.
Results
A total of 1348 patients were divided into R-INH (n = 108), R-NINH (n = 371), and NR (n = 869). Forty-seven patients (3.49%) developed TB with an incidence rate of 16.0 per 1000 person-years. Compared to NR, the TB incidence in R-INH was not statistically different (hazard ratios, 0.55, 95% confidence interval, 0.07–4.21, P = 0.564), whereas it was significantly higher in R-NINH (hazard ratios, 5.04, 95% confidence interval, 2.64–9.62, P < 0.001). The median time from transplantation to TB was 19 months (interquartile range: 6–39), and 18 patients (38.3%) were diagnosed within 1 year of transplantation. Ninety-four patients (87.0%) completed INH prophylaxis, with adverse events including two cases of hepatotoxicity (1.85%) and one case of peripheral neuritis (0.93%).
Conclusions
A 6-month INH regimen based on TB risk factors is effective and well-tolerated for preventing post-transplant TB in kidney transplant recipients.
{"title":"Isoniazid prophylaxis based on tuberculosis risk factors in living kidney transplantation recipients: A retrospective cohort study","authors":"Hao Zhang , Jun Zeng , Tingting Zhu , Tao Lin , Turun Song","doi":"10.1016/j.ijantimicag.2024.107375","DOIUrl":"10.1016/j.ijantimicag.2024.107375","url":null,"abstract":"<div><h3>Background</h3><div>Tuberculosis (TB) is a major and severe opportunistic infection among solid organ transplant recipients. Chemoprophylaxis is advised for those with latent tuberculosis infection. However, the effectiveness of an isoniazid (INH) prophylactic approach based on TB risk factors remains uncertain.</div></div><div><h3>Methods</h3><div>This study included all living-donor kidney transplant recipients between January 2016 and December 2022. The recipients were categorized into three groups: the risk group with INH (R-INH), the risk group without INH (R-NINH), and the non-risk group (NR), based on the presence of TB risk factors and INH usage. The R-INH group received a 6-month INH prophylactic regimen to prevent post-transplant TB infection. The incidence of active TB among the groups was assessed.</div></div><div><h3>Results</h3><div>A total of 1348 patients were divided into R-INH (<em>n</em> = 108), R-NINH (<em>n</em> = 371), and NR (<em>n</em> = 869). Forty-seven patients (3.49%) developed TB with an incidence rate of 16.0 per 1000 person-years. Compared to NR, the TB incidence in R-INH was not statistically different (hazard ratios, 0.55, 95% confidence interval, 0.07–4.21, <em>P</em> = 0.564), whereas it was significantly higher in R-NINH (hazard ratios, 5.04, 95% confidence interval, 2.64–9.62, <em>P</em> < 0.001). The median time from transplantation to TB was 19 months (interquartile range: 6–39), and 18 patients (38.3%) were diagnosed within 1 year of transplantation. Ninety-four patients (87.0%) completed INH prophylaxis, with adverse events including two cases of hepatotoxicity (1.85%) and one case of peripheral neuritis (0.93%).</div></div><div><h3>Conclusions</h3><div>A 6-month INH regimen based on TB risk factors is effective and well-tolerated for preventing post-transplant TB in kidney transplant recipients.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 6","pages":"Article 107375"},"PeriodicalIF":4.9,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-31DOI: 10.1016/j.ijantimicag.2024.107371
Le Fu , Xu Zheng , Jiawen Luo , Yiyu Zhang , Xue Gao , Li Jin , Wenting Liu , Chaoqun Zhang , Dongyu Gao , Bocheng Xu , Qingru Jiang , Shuli Chou , Liang Luo
Objectives
Skin injuries and infections are an inevitable part of daily human life, particularly with chronic wounds, becoming an increasing socioeconomic burden. In treating skin infections and promoting wound healing, bioactive peptides may hold significant potential, particularly those possessing antimicrobial and anti-inflammatory properties. However, obtaining these peptides solely through traditional wet laboratory experiments is costly and time-consuming, and peptides identified by current computer-assisted predictive models largely lack validation of their effects via wet laboratory experiments. Consequently, this study aimed to integrate computer-assisted methods and traditional wet laboratory experiments to identify anti-inflammatory and antimicrobial peptides.
Methods
We developed a computer-assisted mining pipeline to screen potential peptides from the epitopes of the major histocompatibility complex class II.
Results
The peptide AIMP1 was identified, with the ability to physically damage Escherichia coli by increasing bacterial cell membrane permeability, and with the ability to inhibit inflammation by binding to endotoxin-lipopolysaccharide. Additionally, in an LPS-induced inflammation animal model, AIMP1 slightly increased levels of proinflammatory cytokines (TNF-α, IL-1β, and IL-6), and in a skin wound infection animal model, AIMP1 effectively accelerated healing, reduced levels of these pro-inflammatory cytokines, and showed no acute hepatotoxicity or nephrotoxicity.
Conclusions
In conclusion, this study not only developed a computer-assisted mining pipeline for identifying anti-inflammatory and antimicrobial peptides but also successfully pinpointed the peptide AIMP1, demonstrating its therapeutic potential for skin injury treatment.
{"title":"Machine learning accelerates the discovery of epitope-based dual-bioactive peptides against skin infections","authors":"Le Fu , Xu Zheng , Jiawen Luo , Yiyu Zhang , Xue Gao , Li Jin , Wenting Liu , Chaoqun Zhang , Dongyu Gao , Bocheng Xu , Qingru Jiang , Shuli Chou , Liang Luo","doi":"10.1016/j.ijantimicag.2024.107371","DOIUrl":"10.1016/j.ijantimicag.2024.107371","url":null,"abstract":"<div><h3>Objectives</h3><div>Skin injuries and infections are an inevitable part of daily human life, particularly with chronic wounds, becoming an increasing socioeconomic burden. In treating skin infections and promoting wound healing, bioactive peptides may hold significant potential, particularly those possessing antimicrobial and anti-inflammatory properties. However, obtaining these peptides solely through traditional wet laboratory experiments is costly and time-consuming, and peptides identified by current computer-assisted predictive models largely lack validation of their effects via wet laboratory experiments. Consequently, this study aimed to integrate computer-assisted methods and traditional wet laboratory experiments to identify anti-inflammatory and antimicrobial peptides.</div></div><div><h3>Methods</h3><div>We developed a computer-assisted mining pipeline to screen potential peptides from the epitopes of the major histocompatibility complex class II.</div></div><div><h3>Results</h3><div>The peptide AIMP1 was identified, with the ability to physically damage <em>Escherichia coli</em> by increasing bacterial cell membrane permeability, and with the ability to inhibit inflammation by binding to endotoxin-lipopolysaccharide. Additionally, in an LPS-induced inflammation animal model, AIMP1 slightly increased levels of proinflammatory cytokines (TNF-α, IL-1β, and IL-6), and in a skin wound infection animal model, AIMP1 effectively accelerated healing, reduced levels of these pro-inflammatory cytokines, and showed no acute hepatotoxicity or nephrotoxicity.</div></div><div><h3>Conclusions</h3><div>In conclusion, this study not only developed a computer-assisted mining pipeline for identifying anti-inflammatory and antimicrobial peptides but also successfully pinpointed the peptide AIMP1, demonstrating its therapeutic potential for skin injury treatment.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 6","pages":"Article 107371"},"PeriodicalIF":4.9,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-30DOI: 10.1016/j.ijantimicag.2024.107373
Wenhao Wu , Shuangling Ni , Yi Zheng , Piaopiao Zhang , Yan Jiang , Xi Li , Yunsong Yu , Tingting Qu
Hypervirulent Klebsiella pneumoniae (hvKp) poses a serious public health threat. Gas gangrene caused by hvKp is rarely reported and potentially results in a poor prognosis. This study describes the case of a hospitalised patient with gas gangrene and sepsis caused by hvKP. Carbapenem-susceptible hypervirulent Klebsiella pneumoniae (CS-hvKp) strains KPLSN and KPLSX were isolated from the knee joint pus and blood specimens of the patient for further investigations. Whole genome sequencing revealed that KPLSN and KPLSX were highly homologous (single nucleotide polymorphisms [SNPs]<10) and belonged to ST412/K57. The minimum inhibitory concentration and minimum bactericidal concentration under biofilm values of meropenem in KPLSN and KPLSX were significantly higher than in the planktonic state (>128 mg/L vs. 0.25 mg/L, P<0.0001). These two strains had high biofilm formation ability, and the results from fluorescence staining experiments showed that they were not easily killed by meropenem in the biofilm state. KPLSN and KPLSX showed high capsule production and were confirmed to have high virulence through experiments with the Galleria mellonella infection model and the BALB/c mice abdominal infection model. The persistent symptoms may be due to enhanced biofilm and capsule formation. Phylogenetic analysis of global ST412 strains showed their evolution towards higher virulence and resistance. These results emphasise the critical need for judicious antibiotic use and novel therapeutic approaches to combat special infections caused by these pathogens.
{"title":"Hypervirulent Carbapenem-Susceptible Klebsiella pneumoniae ST412/K57 with Strong Biofilm Formation: Association with gas gangrene and sepsis","authors":"Wenhao Wu , Shuangling Ni , Yi Zheng , Piaopiao Zhang , Yan Jiang , Xi Li , Yunsong Yu , Tingting Qu","doi":"10.1016/j.ijantimicag.2024.107373","DOIUrl":"10.1016/j.ijantimicag.2024.107373","url":null,"abstract":"<div><div>Hypervirulent <em>Klebsiella pneumoniae</em> (hvKp) poses a serious public health threat. Gas gangrene caused by hvKp is rarely reported and potentially results in a poor prognosis. This study describes the case of a hospitalised patient with gas gangrene and sepsis caused by hvKP. Carbapenem-susceptible hypervirulent <em>Klebsiella pneumoniae</em> (CS-hvKp) strains KPLSN and KPLSX were isolated from the knee joint pus and blood specimens of the patient for further investigations. Whole genome sequencing revealed that KPLSN and KPLSX were highly homologous (single nucleotide polymorphisms [SNPs]<10) and belonged to ST412/K57. The minimum inhibitory concentration and minimum bactericidal concentration under biofilm values of meropenem in KPLSN and KPLSX were significantly higher than in the planktonic state (>128 mg/L vs. 0.25 mg/L, <em>P</em><0.0001). These two strains had high biofilm formation ability, and the results from fluorescence staining experiments showed that they were not easily killed by meropenem in the biofilm state. KPLSN and KPLSX showed high capsule production and were confirmed to have high virulence through experiments with the <em>Galleria mellonella</em> infection model and the BALB/c mice abdominal infection model. The persistent symptoms may be due to enhanced biofilm and capsule formation. Phylogenetic analysis of global ST412 strains showed their evolution towards higher virulence and resistance. These results emphasise the critical need for judicious antibiotic use and novel therapeutic approaches to combat special infections caused by these pathogens.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 6","pages":"Article 107373"},"PeriodicalIF":4.9,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-29DOI: 10.1016/j.ijantimicag.2024.107369
Sujin An , Jeein Oh , Hoh-Jeong Shon , Jaehwan Song , Youn Soo Choi , Donghyun Kim
Objectives
This study investigates the synergistic effect of combining the TLR7 agonist Imiquimod with either the Nod2 agonist (muramyl dipeptide; MDP) or commensal bacteria as nasal vaccine adjuvants to enhance immunity against respiratory viruses.
Methods
Mice assessed immune responses, including antibody and cytokine profiles, after intranasal immunization with antigen and adjuvant combinations. BMDCs were cultured with these components to measure cytokine production. Germinal center formation and hapten-specific antibodies were evaluated using OT-II T-cell transfer and hapten-ovalbumin. Commensal bacteria from healthy nasal cavities were screened for Nod2-stimulating activity using a reporter assay. Protective efficacy against viral pathogens was evaluated using an influenza A infection model and a pseudovirus system for SARS-CoV-2 neutralizing antibodies.
Results
Screening identified Imiquimod as a potent enhancer of adaptive immune responses during nasal immunization, showing synergy with MDP. This combination elevated IL-12p40 and IL-6 levels, enhanced antibody production, and promoted T follicular helper cell differentiation. The Imiquimod-MDP combination provided robust protection against influenza and SARS-CoV-2. Screening of commensal bacteria revealed differential Nod2-stimulating capacities, with Staphylococcus aureus exhibiting superior synergy with Imiquimod compared to Staphylococcus epidermidis. Notably, this synergism was abolished in Nod2-deficient mice, and pretreatment with S. aureus significantly enhanced the protective efficacy of Imiquimod against influenza compared to S. epidermidis.
Conclusions
Combining Imiquimod with MDP or high Nod2-stimulating bacteria offers a promising strategy for nasal vaccine adjuvants. These combinations effectively boost humoral and cellular immune responses, providing strong protection against respiratory viruses.
{"title":"Co-adjuvanting Nod2-stimulating bacteria with a TLR7 agonist elicits potent protective immunity against respiratory virus infection","authors":"Sujin An , Jeein Oh , Hoh-Jeong Shon , Jaehwan Song , Youn Soo Choi , Donghyun Kim","doi":"10.1016/j.ijantimicag.2024.107369","DOIUrl":"10.1016/j.ijantimicag.2024.107369","url":null,"abstract":"<div><h3>Objectives</h3><div>This study investigates the synergistic effect of combining the TLR7 agonist Imiquimod with either the Nod2 agonist (muramyl dipeptide; MDP) or commensal bacteria as nasal vaccine adjuvants to enhance immunity against respiratory viruses.</div></div><div><h3>Methods</h3><div>Mice assessed immune responses, including antibody and cytokine profiles, after intranasal immunization with antigen and adjuvant combinations. BMDCs were cultured with these components to measure cytokine production. Germinal center formation and hapten-specific antibodies were evaluated using OT-II T-cell transfer and hapten-ovalbumin. Commensal bacteria from healthy nasal cavities were screened for Nod2-stimulating activity using a reporter assay. Protective efficacy against viral pathogens was evaluated using an influenza A infection model and a pseudovirus system for SARS-CoV-2 neutralizing antibodies.</div></div><div><h3>Results</h3><div>Screening identified Imiquimod as a potent enhancer of adaptive immune responses during nasal immunization, showing synergy with MDP. This combination elevated IL-12p40 and IL-6 levels, enhanced antibody production, and promoted T follicular helper cell differentiation. The Imiquimod-MDP combination provided robust protection against influenza and SARS-CoV-2. Screening of commensal bacteria revealed differential Nod2-stimulating capacities, with <em>Staphylococcus aureus</em> exhibiting superior synergy with Imiquimod compared to <em>Staphylococcus epidermidis</em>. Notably, this synergism was abolished in Nod2-deficient mice, and pretreatment with <em>S. aureus</em> significantly enhanced the protective efficacy of Imiquimod against influenza compared to <em>S. epidermidis</em>.</div></div><div><h3>Conclusions</h3><div>Combining Imiquimod with MDP or high Nod2-stimulating bacteria offers a promising strategy for nasal vaccine adjuvants. These combinations effectively boost humoral and cellular immune responses, providing strong protection against respiratory viruses.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 6","pages":"Article 107369"},"PeriodicalIF":4.9,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-29DOI: 10.1016/j.ijantimicag.2024.107370
Wei Liu , Zhiqiang wang , Yanhu Huang , Yuan Liu , Ruichao Li , Mianzhi Wang , Haijie Zhang , Chuang Meng , Xia Xiao
The plasmid-mediated conjugative transfer of antibiotic resistance genes (ARGs) stands out as the primary driver behind the dissemination of antimicrobial resistance (AMR). Developing effective inhibitors that target conjugative transfer represents an potential strategy for addressing the issue of AMR. Here, we studied the effect of acetylshikonin (ASK), a botanical derivative, on plasmid conjugation. The conjugative transfer of RP4-7 plasmid inter and intra species was notably reduced by ASK. The conjugation process of IncI2 and IncX4 plasmids harbouring the mobile colistin resistance gene (mcr-1), IncX4 and IncX3 plasmids containing the carbapenem resistance gene (blaNDM-5), and IncFI and IncFII plasmids possessing the tetracycline resistance gene [tet(X4)] were also reduced by ASK. Importantly, the conjugative transfer frequency of mcr-1 positive IncI2 plasmid in mouse peritoneal conjugation model and gut conjugation model was reduced by ASK. The mechanism investigation showed that ASK disrupted the functionality of the bacterial cell membrane. Furthermore, the proton motive force (PMF) was dissipated. In addition, ASK blocked the electron transmission in bacteria's electron transport chain (ETC) through disturbing the quinone interaction, resulting in an insufficient energy supply for conjugation. Collectively, ASK is a potential conjugative transfer inhibitor, providing novel strategies to prevent the spread of AMR.
质粒介导的抗生素耐药性基因（ARGs）共轭转移是抗生素耐药性（AMR）传播的主要驱动力。开发针对共轭转移的有效抑制剂是解决 AMR 问题的有效策略。在这里，我们研究了植物衍生物乙酰紫草素（ASK）对质粒共轭的影响。ASK明显降低了RP4-7质粒在物种间和物种内的共轭转移。ASK还减少了携带可移动的可乐定抗性基因（mcr-1）的IncI2和IncX4质粒、含有碳青霉烯抗性基因（blaNDM-5）的IncX4和IncX3质粒以及拥有四环素抗性基因[tet(X4)]的IncFI和IncFII质粒的共轭过程。重要的是，在小鼠腹膜共轭模型和肠道共轭模型中，ASK降低了mcr-1阳性IncI2质粒的共轭转移频率。机理研究表明，ASK 破坏了细菌细胞膜的功能。此外，质子动力（PMF）也被耗散。此外，ASK 通过干扰醌的相互作用，阻断了细菌电子传递链（ETC）中的电子传递，导致共轭作用的能量供应不足。总之，ASK 是一种潜在的共轭传递抑制剂，为防止 AMR 的传播提供了新的策略。
{"title":"Acetylshikonin reduces the spread of antibiotic resistance via plasmid conjugation","authors":"Wei Liu , Zhiqiang wang , Yanhu Huang , Yuan Liu , Ruichao Li , Mianzhi Wang , Haijie Zhang , Chuang Meng , Xia Xiao","doi":"10.1016/j.ijantimicag.2024.107370","DOIUrl":"10.1016/j.ijantimicag.2024.107370","url":null,"abstract":"<div><div>The plasmid-mediated conjugative transfer of antibiotic resistance genes (ARGs) stands out as the primary driver behind the dissemination of antimicrobial resistance (AMR). Developing effective inhibitors that target conjugative transfer represents an potential strategy for addressing the issue of AMR. Here, we studied the effect of acetylshikonin (ASK), a botanical derivative, on plasmid conjugation. The conjugative transfer of RP4-7 plasmid inter and intra species was notably reduced by ASK. The conjugation process of IncI2 and IncX4 plasmids harbouring the mobile colistin resistance gene (<em>mcr</em>-1), IncX4 and IncX3 plasmids containing the carbapenem resistance gene (<em>bla</em><sub>NDM-5</sub>), and IncFI and IncFII plasmids possessing the tetracycline resistance gene [<em>tet</em>(X4)] were also reduced by ASK. Importantly, the conjugative transfer frequency of <em>mcr</em>-1 positive IncI2 plasmid in mouse peritoneal conjugation model and gut conjugation model was reduced by ASK. The mechanism investigation showed that ASK disrupted the functionality of the bacterial cell membrane. Furthermore, the proton motive force (PMF) was dissipated. In addition, ASK blocked the electron transmission in bacteria's electron transport chain (ETC) through disturbing the quinone interaction, resulting in an insufficient energy supply for conjugation. Collectively, ASK is a potential conjugative transfer inhibitor, providing novel strategies to prevent the spread of AMR.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 6","pages":"Article 107370"},"PeriodicalIF":4.9,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142557794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-28DOI: 10.1016/j.ijantimicag.2024.107365
A. Oliva , A. Curtolo , A. Falletta , F. Sacco , F. Lancellotti , M. Carnevalini , G. Ceccarelli , G. Roma , M. Bufi , G. Magni , G.M. Raponi , M. Venditti , C.M. Mastroianni
Background
Fosfomycin (FOS) is gaining increasing importance as part of combination therapy for the treatment of carbapenem-resistant Acinetobacter baumannii (CRAB) and KPC-producing Klebsiella pneumoniae (KPC-Kp), thanks to its in vitro synergism with several antibiotics, high tissue distribution and good tolerability. We analyzed the effect on 30-day survival of FOS-containing regimens compared to non–FOS-containing regimens in critically ill patients admitted to the intensive care unit with CRAB or KPC-Kp infections. Secondary objectives were to evaluate clinical cure and microbiologic eradication in the FOS vs. the NO-FOS group.
Methods
This was a monocentric retrospective observational study including SARS-Cov2–negative critically ill patients with KPC-Kp or CRAB infection treated with combination antibiotic therapy with or without FOS for ≥48 h (FOS vs. NO-FOS groups, respectively). The primary outcome was 30-day mortality; secondary outcomes were clinical cure and microbiological eradication.
Results
Of the 78 patients analyzed, 26 (33.3%) were men, with a median (IQR) age and Charlson Comorbidity Index (CCI) of 67 years (53–74) and 4 (2–5), respectively. Septic shock was present in 18 patients (23.1%); 37 (47.4%) were receiving FOS, 41 (52.6%) were not receiving FOS; CRAB and KPC-Kp were isolated in 44 (56.4%) and 34 (43.6%) of patients, respectivley. Compared to NO-FOS, patients receiving FOS had a higher clinical cure (89.2% vs. 65.9%, P = 0.017), early (<72 h) improvement (78.4% vs. 52.2%, P = 0.018), microbiological eradication (87.5% vs 62.2%, P = 0.027), and lower 7-, 14- and 30-day mortality (0% vs. 4.6%, P =0.027; 2.7% vs 22%, P = 0.016; and 13.5% vs. 34.2%, P = 0.039, respectively). This effect was particularly evident for infections sustained by KPC-Kp. On multivariable analysis, receiving FOS was independently associated with survival (hazard ratio = 0.29, 95% CI = 0.09-0.93, P = 0.038), confirmed after IPTW (HR = 0.501 95% CI = 0.25-0.98 P = 0.042).
Conclusions
FOS-containing regimens exhibited a higher clinical cure, higher microbiological eradication and reduced mortality compared with regimens not containing FOS in critically ill patients with CRAB and KPC-Kp infections.
{"title":"Efficacy of Fosfomycin-Containing Regimens in Treating Severe Infections Caused by KPC-Producing Klebsiella pneumoniae and Carbapenem-Resistant Acinetobacter baumannii in Critically Ill Patients","authors":"A. Oliva , A. Curtolo , A. Falletta , F. Sacco , F. Lancellotti , M. Carnevalini , G. Ceccarelli , G. Roma , M. Bufi , G. Magni , G.M. Raponi , M. Venditti , C.M. Mastroianni","doi":"10.1016/j.ijantimicag.2024.107365","DOIUrl":"10.1016/j.ijantimicag.2024.107365","url":null,"abstract":"<div><h3>Background</h3><div>Fosfomycin (FOS) is gaining increasing importance as part of combination therapy for the treatment of carbapenem-resistant <em>Acinetobacter baumannii</em> (CRAB) and KPC-producing <em>Klebsiella pneumoniae</em> (KPC-Kp), thanks to its in vitro synergism with several antibiotics, high tissue distribution and good tolerability. We analyzed the effect on 30-day survival of FOS-containing regimens compared to non–FOS-containing regimens in critically ill patients admitted to the intensive care unit with CRAB or KPC-Kp infections. Secondary objectives were to evaluate clinical cure and microbiologic eradication in the FOS vs. the NO-FOS group.</div></div><div><h3>Methods</h3><div>This was a monocentric retrospective observational study including SARS-Cov2–negative critically ill patients with KPC-Kp or CRAB infection treated with combination antibiotic therapy with or without FOS for ≥48 h (FOS vs. NO-FOS groups, respectively). The primary outcome was 30-day mortality; secondary outcomes were clinical cure and microbiological eradication.</div></div><div><h3>Results</h3><div>Of the 78 patients analyzed, 26 (33.3%) were men, with a median (IQR) age and Charlson Comorbidity Index (CCI) of 67 years (53–74) and 4 (2–5), respectively. Septic shock was present in 18 patients (23.1%); 37 (47.4%) were receiving FOS, 41 (52.6%) were not receiving FOS; CRAB and KPC-Kp were isolated in 44 (56.4%) and 34 (43.6%) of patients, respectivley. Compared to NO-FOS, patients receiving FOS had a higher clinical cure (89.2% vs. 65.9%, <em>P</em> = 0.017), early (<72 h) improvement (78.4% vs. 52.2%, <em>P</em> = 0.018), microbiological eradication (87.5% vs 62.2%, <em>P</em> = 0.027), and lower 7-, 14- and 30-day mortality (0% vs. 4.6%, <em>P</em> =0.027; 2.7% vs 22%, <em>P</em> = 0.016; and 13.5% vs. 34.2%, <em>P</em> = 0.039, respectively). This effect was particularly evident for infections sustained by KPC-Kp. On multivariable analysis, receiving FOS was independently associated with survival (hazard ratio = 0.29, 95% CI = 0.09-0.93, <em>P</em> = 0.038), confirmed after IPTW (HR = 0.501 95% CI = 0.25-0.98 <em>P</em> = 0.042).</div></div><div><h3>Conclusions</h3><div>FOS-containing regimens exhibited a higher clinical cure, higher microbiological eradication and reduced mortality compared with regimens not containing FOS in critically ill patients with CRAB and KPC-Kp infections.</div></div>","PeriodicalId":13818,"journal":{"name":"International Journal of Antimicrobial Agents","volume":"64 6","pages":"Article 107365"},"PeriodicalIF":4.9,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号