Microbial drug resistance最新文献

Methicillin-resistant Staphylococcus aureus (MRSA) infections pose serious treatment challenges, particularly in peritoneal dialysis patients due to their increased susceptibility to infections and antibiotic resistance. Vancomycin, a standard antibiotic treatment for MRSA, is currently being compromised due to the evolution of multidrug-resistant microorganisms. Therefore, there is an urgent need for alternative therapeutic strategies to obstruct the increasing antibiotic resistance and bacterial biofilm formation. The present study explores curcumin, a natural bioactive compound possessing antimicrobial and anti-inflammatory properties, as a potential therapeutic for MRSA. The standard optical density method confirmed the antibacterial activity of curcumin against Staphylococcus aureus (MTCC-3160). Furthermore, we investigated the impact of curcumin on bacterial metabolism. Metabolic analysis of S. aureus culture media over a 20-h period revealed that curcumin exerts bacteriostatic effects by inhibiting specific metabolic pathways, potentially linked to energy and sugar metabolism. Furthermore, the synergistic effect of curcumin combined with vancomycin was assessed against 20 clinical MRSA strains using the broth microdilution method. The results demonstrated that curcumin enhanced the antibacterial activity of vancomycin in 17 strains by reducing its minimum inhibitory concentration (MIC) significantly. The MIC of curcumin and vancomycin has been found to decrease significantly when used in combination, with curcumin's MIC decreased to as low as 0.5 µg/mL and vancomycin's MIC to 0.5 µg/mL for all strains. Synergistic effects were seen in 17 out of 20 strains, having fractional inhibitory concentration index values between 0.04 and 0.56. These findings suggest that curcumin-vancomycin combination therapy could offer an effective treatment strategy for MRSA infections which may combat antibiotic resistance and reduce treatment-related toxicity.

Multidrug-resistant bacterial infections are a rising threat to human health and currently account for 1.3 million deaths annually. Notably, 70% of these deaths are due to gram-negative pathogens, and no new classes of gram-negative-active antibiotics have been approved by the US Food and Drug Administration in the past 55 years. The challenges of converting compounds with in vitro biochemical activity to whole cell gram-negative antibacterial activity are significant, as the outer membrane and promiscuous efflux pumps thwart the potential of most antibiotic candidates. Significant strides have been made toward understanding compound penetration and accumulation in gram-negative bacteria, but efflux remains a major obstacle for antibiotic drug discovery. Recent advances in machine learning (ML) algorithms and increased accessibility of code and programs for the nonexpert suggest artificial intelligence could help address the efflux problem. Here, we discuss work toward understanding efflux and cast a vision for how ML can be utilized to address compound efflux from gram-negative bacteria.

As an opportunistic pathogen, Pseudomonas aeruginosa is often associated with severe respiratory infections. A study conducted in an ICU of a tertiary hospital in Vietnam, where infection management is relatively good, yielded only 18 clinical isolates of P. aeruginosa over 6 months. Though the number is small, treating P. aeruginosa infections is highly complicated. Out of 18 patients, 15 showed no improvement after treatment, leading to worsening conditions or death, possibly due to various factors. High rates of mechanical ventilation (83.3%) may be a contributing factor, suggesting a certain correlation between ventilation and treatment failure. The antibiotic resistance rate in these isolates is relatively high, with a multidrug-resistant rate of 44.4%, resulting in treatment failures when empirical antibiotics are used without susceptibility testing. All isolates have the ability to form biofilms. Moreover, bacteria in stationary phase or within biofilms exhibited poor responses to meropenem and amikacin (about 10% of bacteria survive after antibiotic exposure). Conversely, ciprofloxacin shows much better efficacy, indicating that fluoroquinolones should be used in combination therapy for P. aeruginosa infection to eliminate persistent cells and biofilm-embedded microorganisms, thus enhancing treatment effectiveness.

Carbapenem and colistin-resistant Klebsiella pneumoniae pose a significant threat to public health, particularly in intensive care units, due to high morbidity and mortality rates. This study aimed to analyze five NDM carbapenemase-producing multidrug-resistant K. pneumoniae isolates from different hospitals. Antimicrobial susceptibility testing, hypermucoviscosity analysis, biofilm production assessment, MLST, PCR, and whole-genome sequencing were conducted. All isolates harbored NDM-5 metallo-β-lactamase, belonging to MLST 307, were biofilm producers and exhibited a stop codon (Q30) along MgrB. Genomic analysis revealed multiple-replicon plasmids carrying resistance genes, notably bla_NDM-5, bla_CTX-M-15, rmtB, and qnrB1, with complex genetic structures encoding several mobile genetic elements, including the Tn3 family and IS26. All isolates harbored wzi173 (capsule-locus KL102), iutA (a siderophore-associated gene), and the type 3 fimbriae mrkABCDFHIJ operon. The core genome single nucleotide polymorphisms (SNPs) analysis suggests the circulation of two strains of ST307 clone (SNPs range differences 4-77). These findings highlight the potential plasticity of the high-risk ST307 clone and the urgent need for surveillance and intervention strategies to combat antimicrobial resistance. To our knowledge, this is the first report of K. pneumoniae ST307 carrying bla_NDM-5 and the first description of ST307 in Uruguay. The presence of bla_NDM-5 and pan-aminoglycoside resistance rmtB genes are identified for the first time in Uruguay.

Colistin- and carbapenem-resistant Klebsiella pneumoniae (ColR CrKp) cause important health problems in pediatric intensive care units (PICUs) due to its ability to harbor multiple resistance genes and spread of high-risk clones. In this study, molecular epidemiological characteristics, transferable resistance genes, and mgrB alterations of ColR CrKp isolated from PICU were investigated. Isolates were identified by MALDI-TOF MS, and antimicrobial susceptibility tests were performed using disk diffusion method, gradient strip test, and broth microdilution method. Extended spectrum beta-lactamase, AmpC beta-lactamase, carbapenemase, 16S rRNA methyltransferase, plasmid-mediated quinolone resistance, and mcr-1 to -5 genes were investigated by polymerase chain reaction. Sanger sequencing was performed to obtain bla_OXA-48-like and mgrB sequences. Pulsed-field gel electrophoresis and multilocus sequence typing were used to determine the clonal spread of the isolates. Ten ColR CrKp harboring bla_OXA-48 (70%), bla_OXA-232 (20%), bla_CTX-M (90%), armA (20%), qnrB (20%), and qnrS (50%) were identified. No mcr genes were found, whereas mgrB mutations through modifications (A7T, C88T, and A121G) and insertion of an IS-1-like insertion sequence were determined. Isolates belonged to ST 14, ST 37, ST 101, ST 147, ST 661, ST 985, and ST 2096. It is crucial to determine the antimicrobial resistance properties and the clonal spread of the isolates to guide the treatment decisions, implement effective infection control measures, and develop novel antimicrobial strategies.

Streptococcus anginosus is an important cause of pyogenic infections, bacteremia, and chronic maxillary sinusitis. Mobile genetic elements (MGEs) play a key role in lateral gene transfer, resulting in broad transfer of antibiotic resistance genes (ARGs). However, studies on ARG-associated MGEs in S. anginosus are still rare. To fill this gap, we used sequencing data from 11 clinical S. anginosus to characterize their mobilome diversity through comparative analysis. We found 47 well-characterized MGEs, including 23 putative integrative and conjugative elements (ICEs), 16 prophages/integrative mobilizable elements, and 8 composites. They were inserted into 16 positions, 4 of which were hot spots. A comprehensive analysis revealed that ARG-associated ICEs belong to four groups as follows: single serine integrases (ICESan49.2), tyrosine integrases (ICESan26.2), triple serine integrase ICEs (ICESan195.1), and a putative transposon integrase (ICESan49.1), all of which were similar to ICEs/transposons widely distributed among other streptococci. The eight composites were composed of multiple ICEs or transposons through successive accretion events (tandem or/and internal integration). In conclusion, we found that S. anginosus accumulates a variety of ARG-associated ICE/composites that may enable S. anginosus to serve as an ARG-associated MGE repository for other streptococci. The analysis of composites here provides a paradigm to further study mobilome evolution.

Supplements with their own beneficial effect on hosts are consumed by us. N-acetyl cysteine (NAC) and Vitamin C (Vit C) are antioxidants and supplements, consumed for their beneficial properties. The present investigation evaluates the effect of their antioxidant property on antibiotic efficacy against Escherichia coli cells from different physiological states, including exponential and stationary-phase, cell aggregates, and in-vitro stress-induced persister cells. Survival was measured in cfu/mL by cfu (colony-forming unit) counting, with efficacy determined by log-fold change in survival by comparing CFUs in antibiotics alone and antibiotic + antioxidant combinations. Fluoroquinolones in the presence of NAC reduced ∼1 log CFUs of log-phase and persister cells, while Vit C reduced CFUs (∼1-3-log increase) of cells from all physiological states. Aminoglycosides results were inconclusive; streptomycin's activity declined (∼1-3-log increase in survival), whereas amikacin's activity potentiated (∼1-log reduction in cfu/mL). Rifampicin's showed reduced activity (∼2-3 log increase in survival) with Vit C in all the states and a ∼1-2 log increase with NAC, especially in cell aggregates and persisters. Beta-lactams activity showed variability, with amoxicillin and ampicillin not being influenced, but ceftriaxone showed significant reduction of efficacy (∼2-3-log increase in survival) in all the treatments. The findings suggest that the overall impact of antioxidants on antibiotic efficacy varies depending on the antibiotic class.

Even if in the past years new effective, safe, and orally administrable drugs are available to create shorter regimens, drug-resistant (DR) tuberculosis (TB) treatment remains a critical issue and a major challenge faced by clinicians worldwide. We present the first case of transborder pulmonary pre-extensively drug-resistant (pre-XDR)-TB treated in Italy with the bedaquiline-pretomanid-linezolid regimen. Diagnosis and treatment were started in Ukraine, and, after a month of treatment, due to the Russo-Ukrainian war, the patient moved to Italy, where the diagnosis was confirmed both by genotypic and phenotypic drug susceptibility tests, and treatment continued. In this short report, we highlight challenges and future opportunities to improve the clinical management of patient with DR-TB.

Carbapenenemase producers, particularly the metallo-β-lactamase (MBL) types in Pseudomonas aeruginosa, have emerged as an urgent threat in health care settings. MBLs require zinc at their catalytic site and can be inhibited by dimercaptosuccinic acid (DMSA), a metal chelator known for the treatment of lead and mercury intoxication. Isogenic strains of wild-type and OprD-deleted P. aeruginosa PA14, were constructed, producing the MBLs VIM-2, NDM-1, SPM-1, IMP-1, and AIM-1, or the non-MBL carbapenemases, GES-5 and KPC-2. In addition, 59 previously characterized clinical isolates of P. aeruginosa producing different ß-lactamases (including carbapenemases), and with known outer-membrane porin OprD status, were utilized. Minimal inhibitory concentrations values of imipenem and meropenem, and DMSA combinations were determined, and time-kill assays were performed with PA14 expressing VIM-2. Results indicated a significant additive effect of DMSA (most effective at 3 mM) and carbapenems in recombinant and clinical strains of P. aeruginosa expressing MBLs, in particular against VIM producers, which are the most prevalent carbapenemases in P. aeruginosa. This effect was best evidenced with meropenem and in strains without OprD modification. DMSA shows promising efficacy, particularly in combination therapy with meropenem, for treating infections caused by MBL-producing P. aeruginosa.