Добірка наукової літератури з теми "DRVE resistance-microbial"

Abstract Background and objectives Slowing the spread of antimicrobial resistance is urgent if we are to continue treating infectious diseases successfully. There is increasing evidence microbial interactions between and within species are significant drivers of resistance. On one hand, cross-protection by resistant genotypes can shelter susceptible microbes from the adverse effects of antibiotics, reducing the advantage of resistance. On the other hand, antibiotic-mediated killing of susceptible genotypes can alleviate competition and allow resistant strains to thrive (competitive release). Here, by observing interactions both within and between species in microbial communities sampled from humans, we investigate the potential role for cross-protection and competitive release in driving the spread of ampicillin resistance in the ubiquitous gut commensal and opportunistic pathogen Escherichia coli. Methodology Using anaerobic gut microcosms comprising E.coli embedded within gut microbiota sampled from humans, we tested for cross-protection and competitive release both within and between species in response to the clinically important beta-lactam antibiotic ampicillin. Results While cross-protection gave an advantage to antibiotic-susceptible E.coli in standard laboratory conditions (well-mixed LB medium), competitive release instead drove the spread of antibiotic-resistant E.coli in gut microcosms (ampicillin boosted growth of resistant bacteria in the presence of susceptible strains). Conclusions and implications Competition between resistant strains and other members of the gut microbiota can restrict the spread of ampicillin resistance. If antibiotic therapy alleviates competition with resident microbes by killing susceptible strains, as here, microbiota-based interventions that restore competition could be a key for slowing the spread of resistance. Lay Summary Slowing the spread of global antibiotic resistance is an urgent task. In this paper, we ask how interactions between microbial species drive the spread of resistance. We show that antibiotic killing of susceptible microbes can free up resources for resistant microbes and allow them to thrive. Therefore, we should consider microbes in light of their social interactions to understand the spread of resistance.

Antimicrobial peptides (AMPs) have been proposed as a promising new class of antimicrobials despite warnings that therapeutic use could drive the evolution of pathogens resistant to our own immunity peptides. Using experimental evolution, we demonstrate that Staphylococcus aureus rapidly evolved resistance to pexiganan, a drug-candidate for diabetic leg ulcer infections. Evolved resistance was costly in terms of impaired growth rate, but costs-of-resistance were completely ameliorated by compensatory adaptation. Crucially, we show that, in some populations, experimentally evolved resistance to pexiganan provided S. aureus with cross-resistance to human-neutrophil-defensin-1, a key component of the innate immune response to infection. This unintended consequence of therapeutic use could drastically undermine our innate immune system's ability to control and clear microbial infections. Our results therefore highlight grave potential risks of AMP therapies, with implications for their development.

Despite occurring at the microscopic scale, the armed race between phages and their bacterial hosts involves multiple mechanisms, some of which are just starting to be understood. On the one hand, bacteria have evolved strategies that can stop the viral infection at different stages (adsorption, DNA injection and replication, biosynthesis and assembly of the viral progeny and/or release of the newly formed virions); on the other, phages have gradually evolved counterattack strategies that allow them to continue infecting their prey. This co-evolutionary process has played a major role in the development of microbial populations in both natural and man-made environments. Notably, understanding the parameters of this microscopic war will be paramount to fully benefit from the application of phage therapy against dangerous, antibiotic-resistant human pathogens. This review gathers the current knowledge regarding the mechanisms of phage resistance in the Staphylococcus genus, which includes Staphylococcus aureus, one of the most concerning microorganisms in terms of antibiotic resistance acquisition. Some of these strategies involve permanent changes to the bacterial cell via mutations, while others are transient, adaptive changes whose expression depends on certain environmental cues or the growth phase. Finally, we discuss the most plausible strategies to limit the impact of phage resistance on therapy, with a special emphasis on the importance of a rational design of phage cocktails in order to thwart therapeutic failure.

The drug resistance of microorganisms has been a serious threat to public health for several decades. The growing problem of opportunistic infections in recent years and the wide access to antimicrobial drugs in both human and animal medicine determine and drive the complex mechanism related to the spread of antimicrobial resistance. Nevertheless, this phenomenon does not result only from certain practices related to the intensification of livestock production in recent years, which is often indicated as the main cause. Understanding the mechanisms and consequences of drug resistance requires not only the assessment of its contemporary causes, but also a retrospective look and an analysis why modern medicine, despite its extensive research capabilities and profound knowledge, continues to struggle with the problem of microbial insensitivity to most antimicrobials available today. This problem should be considered in the very broad context of the doctrine of “One Health”, which includes the dependence in the interconnected system of human–animal–environment.

Antimicrobial resistance (AMR) is a threat to animal and human health. Antimicrobial use has been identified as a major driver of AMR, and reductions in use are a focal point of interventions to reduce resistance. Accordingly, stakeholders in human health and livestock production have implemented antimicrobial stewardship programs aimed at reducing use. Thus far, these efforts have yielded variable impacts on AMR. Furthermore, scientific advances are prompting an expansion and more nuanced appreciation of the many nonantibiotic factors that drive AMR, as well as how these factors vary across systems, geographies, and contexts. Given these trends, we propose a framework to prioritize AMR interventions. We use this framework to evaluate the impact of interventions that focus on antimicrobial use. We conclude by suggesting that priorities be expanded to include greater consideration of host–microbial interactions that dictate AMR, as well as anthropogenic and environmental systems that promote dissemination of AMR.

ABSTRACT Resistance to antimicrobial drugs used to treat bacterial, viral, fungal and parasitic infections is a major health concern requiring a coordinated response across the globe. An important aspect in the fight against antimicrobial resistance is the development of novel drugs that are effective against resistant pathogens. Drug development is a complex trans-disciplinary endeavor, in which structural biology plays a major role by providing detailed functional and mechanistic information on an antimicrobial target and its interactions with small molecule inhibitors. Although X-ray crystallography and nuclear magnetic resonance have until now been the methods of choice to characterize microbial targets and drive structure-based drug development, cryo-electron microscopy is rapidly gaining ground in these areas. In this perspective, we will discuss how cryo-electron microscopy is changing our understanding of an established antimicrobial target, the ribosome, and how methodological developments could help this technique become an integral part of the antimicrobial drug discovery pipeline.

AbstractKlebsiella spp. that secrete the DNA-alkylating enterotoxin tilimycin colonize the human intestinal tract. Numbers of toxigenic bacteria increase during antibiotic use, and the resulting accumulation of tilimycin in the intestinal lumen damages the epithelium via genetic instability and apoptosis. Here we examine the impact of this genotoxin on the gut ecosystem. 16S rRNA sequencing of faecal samples from mice colonized with Klebsiella oxytoca strains and mechanistic analyses show that tilimycin is a pro-mutagenic antibiotic affecting multiple phyla. Transient synthesis of tilimycin in the murine gut antagonized niche competitors, reduced microbial richness and altered taxonomic composition of the microbiota both during and following exposure. Moreover, tilimycin secretion increased rates of mutagenesis in co-resident opportunistic pathogens such as Klebsiella pneumoniae and Escherichia coli, as shown by de novo acquisition of antibiotic resistance. We conclude that tilimycin is a bacterial mutagen, and flares of genotoxic Klebsiella have the potential to drive the emergence of resistance, destabilize the gut microbiota and shape its evolutionary trajectory.

Interferon (IFN)-inducible guanylate binding proteins (GBPs) mediate cell-autonomous host resistance to bacterial pathogens and promote inflammasome activation. The prevailing model postulates that these two GBP-controlled activities are directly linked through GBP-dependent vacuolar lysis. It was proposed that the rupture of pathogen-containing vacuoles (PVs) by GBPs destroyed the microbial refuge and simultaneously contaminated the host cell cytosol with microbial activators of inflammasomes. Here, we demonstrate that GBP-mediated host resistance and GBP-mediated inflammatory responses can be uncoupled. We show that PVs formed by the rodent pathogenChlamydia muridarum, so-called inclusions, remain free of GBPs and thatC. muridarumis impervious to GBP-mediated restrictions on bacterial growth. Although GBPs neither bind toC. muridaruminclusions nor restrictC. muridarumgrowth, we find that GBPs promote inflammasome activation inC. muridarum-infected macrophages. We demonstrate thatC. muridaruminfections induce GBP-dependent pyroptosis through both caspase-11-dependent noncanonical and caspase-1-dependent canonical inflammasomes. Among canonical inflammasomes, we find thatC. muridarumand the human pathogenChlamydia trachomatisactivate not only NLRP3 but also AIM2. Our data show that GBPs support fast-kinetics processing and secretion of interleukin-1β (IL-1β) and IL-18 by the NLRP3 inflammasome but are dispensable for the secretion of the same cytokines at later times postinfection. Because IFN-γ fails to induce IL-1β transcription, GBP-dependent fast-kinetics inflammasome activation can drive the preferential processing of constitutively expressed IL-18 in IFN-γ-primed macrophages in the absence of prior Toll-like receptor stimulation. Together, our results reveal that GBPs control the kinetics of inflammasome activation and thereby shape macrophage responses toChlamydiainfections.

Aim: The thesis reports the outcomes of a systematic review conducted to identify the risk factors associated with antimicrobial resistant organism (ARO) carriage in residents of residential aged care facilities (RACF). Background: The World Health Organization (WHO) recognises antimicrobial resistance as a critical world health issue and acknowledges that with the reduction in the development of new antibiotics there is an urgent need to take action to slow the spread of antimicrobial resistant organisms (AROs). Residential Aged Care Facilities (RACFs) aim to provide nursing and personal care to the elderly who can no longer remain in their own home; in an environment that is safe and home-like. AROs are commonly found in aged care settings. A resident who is infected or colonised with an ARO may be a temporary or longer-term carrier of an ARO, and may act as a reservoir for the organism and a potential source of transmission to others. A risk-management approach is required in order to implement effective infection prevention strategies for dealing with residents with AROs. All facilities need to be able to identify the risks in their own context and select the appropriate course of action; however, little is known about the risk factors for ARO acquisition in this population. Method: A comprehensive literature search was conducted of Medline, Cumulative Index to Nursing and Allied Health Literature (CINHAL), Embase and Cochrane databases for quantitative studies that examined the risk factors for carriage of AROs in residents of RACFs. All risk factors associated with carriage of any antibiotic resistant organism in the target population were considered in this review. The review followed the Johanna Briggs Institute (JBI) methodology for conducting systematic reviews of quantitative studies. Results: This review considered 32 quantitative studies that met the inclusion criteria and identified risk factors associated with ARO carriage in residents of residential aged care facilities. In all, over seventy potential risk factors were examined in the included studies. Data extracted from these studies were analysed with Comprehensive Meta Analysis (CMA) software. As a result of the meta-analysis a total of 10 statistically significant risk factors that influence the colonisation or infection of residents of RACFs with AROs were identified; • Comorbidities • Immobility • Dependency • Wounds • Incontinence • History of an ARO • Male Sex • Invasive devices • Previous antibiotic therapy • Hospitalisation The results will be presented in detail in the thesis. Conclusions: Of the 10 risk factors identified not all were generalisable to the population as a whole; however some were, and this generalisability will be discussed further in the thesis. This information will inform risk identification and mitigation protocols for use in this setting. It may potentially lead to the development of a reliable risk assessment tool that staff can use to identify those residents most at risk. This review has provided an evidence base on which to build a planned approach to risk management and the implementation of transmission prevention strategies to prevent AROs in residents of RACFs.
Thesis (M.Clin.Sc.) -- University of Adelaide, School of Translational Health Science, 2015.