npj antimicrobials and resistance最新文献

Heteroresistance (HR) in bacteria describes a subpopulational phenomenon of antibiotic resistant cells of a generally susceptible population. Here, we investigated the molecular mechanisms and phenotypic characteristics underlying HR to ceftazidime (CAZ) in a clinical Enterobacter cloacae complex strain (ECC). We identified a plasmid-borne gene duplication-amplification (GDA) event of a region harbouring an ampC gene encoding a β-lactamase bla_DHA-1 as the key determinant of HR. Individual colonies exhibited variations in the copy number of the genes resulting in resistance level variation which correlated with growth onset (lag times) and growth rates in the presence of CAZ. GDA copy number heterogeneity occurred within single resistant colonies, demonstrating heterogeneity of GDA on the single-cell level. The interdependence between GDA, lag time and antibiotic treatment and the strong plasticity underlying HR underlines the high risk for misdetection of antimicrobial HR and subsequent treatment failure.

We assess three words commonly used to represent the environmental dimensions of antimicrobial resistance (AMR) - 'hotspot', 'reservoir' and 'pristine' - through two questions: how are these terms used in published research; and how do these terms shape research being conducted? We advocate for the community to reflect on and improve its use of language, and suggest four potentially more productive and precise terms for AMR hazard: presence; transmission; evolution and connectivity.

Antimicrobial resistance (AMR) is an emerging threat to global public health. Specifically, Acinetobacter baumannii (A. baumannii), one of the main pathogens driving the rise of nosocomial infections, is a Gram-negative bacillus that displays intrinsic resistance mechanisms and can also develop resistance by acquiring AMR genes from other bacteria. More importantly, it is resistant to nearly 90% of standard of care (SOC) antimicrobial treatments, resulting in unsatisfactory clinical outcomes and a high infection-associated mortality rate of over 30%. Currently, there is a growing challenge to sustainably develop novel antimicrobials in this ever-expanding arms race against AMR. Therefore, a sustainable workflow that properly manages healthcare resources to ultra-rapidly design optimal drug combinations for effective treatment is needed. In this study, the IDentif.AI-AMR platform was harnessed to pinpoint effective regimens against four A. baumannii clinical isolates from a pool of nine US FDA-approved drugs. Notably, IDentif.AI-pinpointed ampicillin-sulbactam/cefiderocol and cefiderocol/polymyxin B/rifampicin combinations were able to achieve 93.89 ± 5.95% and 92.23 ± 11.89% inhibition against the bacteria, respectively, and they may diversify the reservoir of treatment options for the indication. In addition, polymyxin B in combination with rifampicin exhibited broadly applicable efficacy and strong synergy across all tested clinical isolates, representing a potential treatment strategy for A. baumannii. IDentif.AI-pinpointed combinations may potentially serve as alternative treatment strategies for A. baumannii.

Antimicrobial resistance (AMR) poses a growing global health threat. Nanomedicine, combined with drug repurposing, may help extend the effective lifespan of current and new antimicrobials. This review, presents an Australian perspective on nanotechnology-based therapies, highlighting scientific and clinical challenges. Early consideration of the potential barriers to market access may help to accelerate research translation, regulatory approval and patient access to nano-antimicrobial (NAM) drugs for resistant pathogens, not only in Australia, but globally.

Salmonella enterica serovar Minnesota (S. Minnesota) is an emerging serovar that persists within poultry supply chains, potentially causing outbreaks in humans. Understanding its population genomics is crucial for designing preventive measures. We performed a genomic surveillance study of S. Minnesota by analyzing 259 isolates from poultry in Saudi Arabia. Whole-genome sequencing data for these isolates were analyzed to characterize emerging clones and the genetic factors underlying antimicrobial resistance and virulence. We compared the isolates to all available global genomes of S. Minnesota. Our results revealed the emergence of four clones, three of which were mixed with global strains. These clones exhibited higher levels of antimicrobial resistance and virulence due to the acquisition of multiple plasmids, particularly IncC plasmids, carrying resistance and virulence genes. IncC plasmids underwent genomic rearrangements, presenting diverse configurations of resistance genes. Our findings demonstrate the emergence and persistence of pathogenic and multidrug-resistant S. Minnesota clones.

Antimicrobial resistance (AMR) is a multifactorial issue involving an intertwining relationship between animals, humans and the environment. The environment can harbour Escherichia coli that are pathogenic or commensal. Escherichia coli is used as an indicator of environmental faecal contamination. Through culture dependent approaches this study identified 46 E. coli isolates in porcine and bovine manure, non-manured and manured soil, and manured grass. The grass isolation highlights grass as an environmental reservoir for E. coli. We also identified a diverse plasmidome with 23 different plasmid replicon types. The E. coli isolates were phenotypically antimicrobial resistant, predominantly multidrug resistant. Whole genome sequencing identified 31 antimicrobial resistance genes, and mutations in the gyrA, parC, and parE genes, conferring fluoroquinolone resistance. This study demonstrates grass as an understudied environmental niche of AMR E. coli, which directly links the environment to the grass grazing animal and vice-versa via the circular economy of manure application.

Bacterial heteroresistance, a phenomenon where subpopulations within a bacterial strain exhibit significantly reduced antibiotic susceptibility compared to the main population, poses a major challenge in managing infectious diseases. It is considered an intermediate stage in the evolution of bacteria towards full resistance. Heteroresistant strains often have a minimal inhibitory concentration (MIC) that appears sensitive, making detection and differentiation in clinical settings difficult. As a result, the impact on clinical outcomes is challenging to fully understand, as it often remains "hidden". In recent years, heteroresistance has received increasing attention. However, it is still poorly understood and underappreciated. We provide an overview of the epidemiology, mechanisms, and clinical impact of heteroresistance. This review underscores the critical importance of understanding and addressing bacterial heteroresistance in the ongoing fight against antibiotic resistance and infectious diseases.

Regulatory elements controlling gene expression fine-tune bacterial responses to environmental cues, including antimicrobials, to optimize survival. Acinetobacter baumannii, a pathogen notorious for antimicrobial resistance, relies on efficient efflux systems. Though the role of efflux systems in antibiotic expulsion are well recognized, the regulatory mechanisms controlling their expression remain understudied. This review explores the current understanding of these regulators, aiming to inspire strategies to combat bacterial resistance and improve therapeutic outcomes.

Since its discovery nearly 60 years ago, TolC has been associated with various cellular functions in Escherichia coli, including the efflux of environmental stressors and virulence factors. It also acts as a receptor for specific bacteriophages and the colicin E1 toxin. This review highlights key discoveries over the past six decades and emphasizes the remaining gaps in understanding how TolC contributes to physiological functions in E. coli.

The genus Nocardia comprises over 130 species of soil-dwelling actinomycetes, many of which are opportunistic pathogens. Beyond their pathogenicity, Nocardia exhibits significant biosynthetic potential, producing an array of diverse antimicrobial secondary metabolites. This review highlights notable examples of these compounds and explores modern approaches to unlocking their untapped biosynthetic potential. As a relatively underexplored genus, Nocardia represents a promising source for new antibiotics to combat the growing resistance crisis.