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"Webber, Mark"
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Molecular mechanisms of antibiotic resistance revisited
Antibiotic resistance is a global health emergency, with resistance detected to all antibiotics currently in clinical use and only a few novel drugs in the pipeline. Understanding the molecular mechanisms that bacteria use to resist the action of antimicrobials is critical to recognize global patterns of resistance and to improve the use of current drugs, as well as for the design of new drugs less susceptible to resistance development and novel strategies to combat resistance. In this Review, we explore recent advances in understanding how resistance genes contribute to the biology of the host, new structural details of relevant molecular events underpinning resistance, the identification of new resistance gene families and the interactions between different resistance mechanisms. Finally, we discuss how we can use this information to develop the next generation of antimicrobial therapies.In this Review, Blair, Webber and colleagues explore our understanding of the mechanisms of antibiotic resistance, including reduced permeability, antibiotic efflux, modification or alteration of the antibiotic target, modification or destruction of the drug itself, and bypass of metabolic pathways. They also discuss how this information can aid in developing the next generation of antimicrobial therapies.
Journal Article
Mechanisms of antimicrobial resistance in biofilms
Most bacteria in nature exist in aggregated communities known as biofilms, and cells within a biofilm demonstrate major physiological changes compared to their planktonic counterparts. Biofilms are associated with many different types of infections which can have severe impacts on patients. Infections involving a biofilm component are often chronic and highly recalcitrant to antibiotic therapy as a result of intrinsic physical factors including extracellular matrix production, low growth rates, altered antibiotic target production and efficient exchange of resistance genes. This review describes the biofilm lifecycle, phenotypic characteristics of a biofilm, and contribution of matrix and persister cells to biofilms intrinsic tolerance to antimicrobials. We also describe how biofilms can evolve antibiotic resistance and transfer resistance genes within biofilms. Multispecies biofilms and the impacts of various interactions, including cooperation and competition, between species on tolerance to antimicrobials in polymicrobial biofilm communities are also discussed.
Journal Article
Molecular mechanisms of antibiotic resistance
Key Points
Antibiotic resistance is a global health emergency.
Resistance mechanisms exist for all current antibiotics, and few new drugs are in development.
Resistance can occur via a reduction in the intracellular concentration of drug, by target site alteration or protection and by the direct inactivation of antibiotics.
The mobilization of resistance genes into pathogens is making the treatment of severe infections challenging owing to a lack of effective antibiotics.
Our understanding of the molecular mechanisms of resistance has recently increased as a result of advances in systems biology, genomics and structural biology.
New knowledge about antibiotic resistance should be used to inform the design of novel therapeutic agents that might not be subject to, or can circumvent, mechanisms of resistance.
Antibiotic-resistant bacteria are causing a global health crisis. Here, the authors review recent advances in our understanding of the mechanisms by which bacteria are either intrinsically resistant or acquire resistance to antibiotics. This information should aid the discovery and development of new compounds that can circumvent or neutralize existing resistance mechanisms.
Antibiotic-resistant bacteria that are difficult or impossible to treat are becoming increasingly common and are causing a global health crisis. Antibiotic resistance is encoded by several genes, many of which can transfer between bacteria. New resistance mechanisms are constantly being described, and new genes and vectors of transmission are identified on a regular basis. This article reviews recent advances in our understanding of the mechanisms by which bacteria are either intrinsically resistant or acquire resistance to antibiotics, including the prevention of access to drug targets, changes in the structure and protection of antibiotic targets and the direct modification or inactivation of antibiotics.
Journal Article
The Antibacterial Activity of Acetic Acid against Biofilm-Producing Pathogens of Relevance to Burns Patients
Localised infections, and burn wound sepsis are key concerns in the treatment of burns patients, and prevention of colonisation largely relies on biocides. Acetic acid has been shown to have good antibacterial activity against various planktonic organisms, however data is limited on efficacy, and few studies have been performed on biofilms.
We sought to investigate the antibacterial activity of acetic acid against important burn wound colonising organisms growing planktonically and as biofilms.
Laboratory experiments were performed to test the ability of acetic acid to inhibit growth of pathogens, inhibit the formation of biofilms, and eradicate pre-formed biofilms.
Twenty-nine isolates of common wound-infecting pathogens were tested. Acetic acid was antibacterial against planktonic growth, with an minimum inhibitory concentration of 0.16-0.31% for all isolates, and was also able to prevent formation of biofilms (at 0.31%). Eradication of mature biofilms was observed for all isolates after three hours of exposure.
This study provides evidence that acetic acid can inhibit growth of key burn wound pathogens when used at very dilute concentrations. Owing to current concerns of the reducing efficacy of systemic antibiotics, this novel biocide application offers great promise as a cheap and effective measure to treat infections in burns patients.
Journal Article
Genomic characterization of Pseudomonas spp. on food: implications for spoilage, antimicrobial resistance and human infection
Background
Pseudomonas
species are common on food, but their contribution to the antimicrobial resistance gene (ARG) burden within food or as a source of clinical infection is unknown.
Pseudomonas aeruginosa
is an opportunistic pathogen responsible for a wide range of infections and is often hard to treat due to intrinsic and acquired ARGs commonly carried by this species. This study aimed to understand the potential role of
Pseudomonas
on food as a reservoir of ARGs and to assess the presence of potentially clinically significant
Pseudomonas aeruginosa
strains on food. To achieve this, we assessed the genetic relatedness (using whole genome sequencing) and virulence of food-derived isolates to those collected from humans.
Results
A non-specific culturing approach for
Pseudomonas
recovered the bacterial genus from 28 of 32 (87.5%) retail food samples, although no
P. aeruginosa
was identified. The
Pseudomonas
species recovered were not clinically relevant, contained no ARGs and are likely associated with food spoilage. A specific culture method for
P. aeruginosa
resulted in the recovery of
P. aeruginosa
from 14 of 128 (11%) retail food samples; isolates contained between four and seven ARGs each and belonged to 16 sequence types (STs), four of which have been isolated from human infections. Food
P. aeruginosa
isolates from these STs demonstrated high similarity to human-derived isolates, differing by 41–312 single nucleotide polymorphisms (SNPs). There were diverse
P. aeruginosa
collected from the same food sample with distinct STs present on some samples and isolates belonging to the same ST differing by 19–67 SNPs. The
Galleria mellonella
infection model showed that 15 of 16 STs isolated from food displayed virulence between a low-virulence (PAO1) and a high virulence (PA14) control.
Conclusion
The most frequent
Pseudomonas
recovered from food examined in this study carried no ARGs and are more likely to play a role in food spoilage rather than infection.
P. aeruginosa
isolates likely to be able to cause human infections and with multidrug resistant genotypes are present on a relatively small but still substantial proportions of retail foods examined. Given the frequency of exposure, the potential contribution of food to the burden of
P. aeruginosa
infections in humans should be evaluated more closely.
Journal Article
Potentiation of curing by a broad-host-range self-transmissible vector for displacing resistance plasmids to tackle AMR
Plasmids are potent vehicles for spread of antibiotic resistance genes in bacterial populations and often persist in the absence of selection due to efficient maintenance mechanisms. We previously constructed non-conjugative high copy number plasmid vectors that efficiently displace stable plasmids from enteric bacteria in a laboratory context by blocking their replication and neutralising their addiction systems. Here we assess a low copy number broad-host-range self-transmissible IncP-1 plasmid as a vector for such curing cassettes to displace IncF and IncK plasmids. The wild type plasmid carrying the curing cassette displaces target plasmids poorly but derivatives with deletions near the IncP-1 replication origin that elevate copy number about two-fold are efficient. Verification of this in mini IncP-1 plasmids showed that elevated copy number was not sufficient and that the parB gene, korB, that is central to its partitioning and gene control system, also needs to be included. The resulting vector can displace target plasmids from a laboratory population without selection and demonstrated activity in a mouse model although spread is less efficient and requires additional selection pressure.
Journal Article