A metabolic perspective into antimicrobial tolerance and resistance.
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ABSTRACT:
SUBMITTER: Bhusal RP
PROVIDER: S-EPMC8794497 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:We combine methodology from history and genetics to reconstruct the biosocial history of antimicrobial resistance (AMR) in the bacterium Salmonella enterica serovar Typhi (S. Typhi). We show how evolutionary divergence in S. Typhi was driven by rising global antibiotic use and by the neglect of typhoid outside of high-income countries. Although high-income countries pioneered 1960s precautionary antibiotic regulations to prevent selection for multidrug resistance, new antibiotic classes, typhoid's cultural status as a supposedly ancient disease of "undeveloped" countries, limited international funding, and narrow biosecurity agendas helped fragment effective global collective action for typhoid control. Antibiotic-intensive compensation for weak water and healthcare systems subsequently fueled AMR selection in low- and middle-income countries but often remained invisible due to lacking surveillance capabilities. The recent rise of extensively drug-resistant typhoid bears the biosocial footprint of more than half a century of antibiotic-intensive international neglect.
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Project description:Antimicrobial resistance and tolerance are natural phenomena that arose due to evolutionary adaptation of microorganisms against various xenobiotic agents. These adaptation mechanisms make the current treatment options challenging as it is increasingly difficult to treat a broad range of infections, associated biofilm formation, intracellular and host adapted microbes, as well as persister cells and microbes in protected niches. Therefore, novel strategies are needed to identify the most promising drug targets to overcome the existing hurdles in the treatment of infectious diseases. Furthermore, discovery of novel drug candidates is also much needed, as few novel antimicrobial drugs have been introduced in the last two decades. In this review, we focus on the strategies that may help in the development of innovative small molecules which can interfere with microbial resistance mechanisms. We also highlight the recent advances in optimization of growth media which mimic host conditions and genome scale molecular analyses of microbial response against antimicrobial agents. Furthermore, we discuss the identification of antibiofilm molecules and their mechanisms of action in the light of the distinct physiology and metabolism of biofilm cells. This review thus provides the most recent advances in host mimicking growth media for effective drug discovery and development of antimicrobial and antibiofilm agents.
| S-EPMC9863313 | biostudies-literature
Project description:A critical challenge for microbiology and medicine is how to cure infections by bacteria that survive antibiotic treatment by persistence or tolerance. Seeking mechanisms behind such high survival, we developed a forward-genetic method for efficient isolation of high-survival mutants in any culturable bacterial species. We found that perturbation of an essential biosynthetic pathway (arginine biosynthesis) in a mycobacterium generated three distinct forms of resistance to diverse antibiotics, each mediated by induction of WhiB7: high persistence and tolerance to kanamycin, high survival upon exposure to rifampicin, and minimum inhibitory concentration-shifted resistance to clarithromycin. As little as one base change in a gene that encodes, a metabolic pathway component conferred multiple forms of resistance to multiple antibiotics with different targets. This extraordinary resilience may help explain how substerilizing exposure to one antibiotic in a regimen can induce resistance to others and invites development of drugs targeting the mediator of multiform resistance, WhiB7.
| S-EPMC8397267 | biostudies-literature
Project description:The urgent necessity to fight antimicrobial resistance is universally recognized. In the search of new targets and strategies to face this global challenge, a promising approach resides in the study of the cellular response to antimicrobial exposure and on the impact of global cellular reprogramming on antimicrobial drugs' efficacy. The metabolic state of microbial cells has been shown to undergo several antimicrobial-induced modifications and, at the same time, to be a good predictor of the outcome of an antimicrobial treatment. Metabolism is a promising reservoir of potential drug targets/adjuvants that has not been fully exploited to date. One of the main problems in unraveling the metabolic response of cells to the environment resides in the complexity of such metabolic networks. To solve this problem, modeling approaches have been developed, and they are progressively gaining in popularity due to the huge availability of genomic information and the ease at which a genome sequence can be converted into models to run basic phenotype predictions. Here, we review the use of computational modeling to study the relationship between microbial metabolism and antimicrobials and the recent advances in the application of genome-scale metabolic modeling to the study of microbial responses to antimicrobial exposure.
| S-EPMC10215601 | biostudies-literature
Project description:Antimicrobial resistance (AMR) occurs when microbes no longer respond to any pharmacological agents, rendering the conventional antimicrobial agents ineffective. AMR has been classified as one of the top 10 life-threatening global health problems needed multilevel attention and global cooperation to attain the Sustainable Development Goals (SDGs) according to the World Health Organization (WHO), making the discovery of a new and effective antimicrobial agent a priority. The recommended treatments for drug-resistant microbes are available but limited. Furthermore, the transformation of microbes over time increases the risk of developing drug resistance. Hence, plant metabolites such as terpenes, phenolic compounds and alkaloids are widely studied due to their antibacterial, antiviral, antifungal and antiparasitic effects. Plant-derived antimicrobials are preferred due to their desirable efficacy and safety profile. Plant metabolites work by targeting microbial cell membranes, interfering with the synthesis of microbial DNA/RNA/enzymes and disrupting quorum sensing and efflux pump expression. They also work synergistically with conventional antibiotics to enhance antimicrobial effects. Accordingly, this review aims to identify currently available pharmacological therapies against microbes and AMR, as well as to discuss the importance of plant and secondary metabolites as a possible solution for AMR together with their mechanisms of action. All the information was obtained from government databases, WHO websites, PubMed, Springer, Google Scholar and Science Direct. Based on the information obtained, AMR is regarded as a significant warning to global healthcare. Plant derivatives such as secondary metabolites may be considered as potential therapeutic targets to mitigate the non-ending AMR.
| S-EPMC9557208 | biostudies-literature
Project description:BackgroundStreptococcus dysgalactiae (SD) is an important pathogen in humans as well as in a broad range of animal species. Escalating rates of antibiotic resistance in SD has been reported in both human and veterinary clinical practice, but the dissemination of resistance determinants has so far never been examined in a One Health Perspective. We wanted to explore the occurrence of zoonotic transmission of SD and the potential for exchange of resistance traits between SD from different host populations.MethodsWe compared whole genome sequences and phenotypical antimicrobial susceptibility of 407 SD isolates, comprising all isolates obtained from human bloodstream infections in 2018 (n = 274) and available isolates associated with animal infections from the years 2018 and 2019 (n = 133) in Norway.ResultsAntimicrobial resistance genes were detected in 70 (26%), 9 (25%) and 2 (2%) of the isolates derived from humans, companion animals and livestock, respectively. Notably, distinct host associated genotypic resistomes were observed. The erm(A) gene was the dominant cause of erythromycin resistance in human associated isolates, whereas only erm(B) and lsa(C) were identified in SD isolates from animals. Moreover, the tetracycline resistance gene tet(O) was located on different mobile genetic elements in SD from humans and animals. Evidence of niche specialization was also evident in the phylogenetic analysis, as the isolates could be almost perfectly delineated in accordance with host species. Nevertheless, near identical mobile genetic elements were observed in four isolates from different host species including one human, implying potential transmission of antibiotic resistance between different environments.ConclusionWe found a phylogenetic delineation of SD strains in line with host adapted populations and niche specialization. Direct transmission of strains or genetic elements carrying resistance genes between SD from different ecological niches appears to be rare in our geographical region.
| S-EPMC11348040 | biostudies-literature
Project description:BACKGROUND:There is worldwide concern of rapidly increasing antimicrobial resistance (AMR). However, there is paucity of resistance surveillance data and updated antibiograms in Africa in general. This study was undertaken in Kenyatta National Hospital (KNH) -the largest public tertiary referral centre in East & Central Africa-to help bridge existing AMR knowledge and practice gaps. METHODS:A retrospective review of VITEK 2 (bioMérieux) records capturing antimicrobial susceptibility data for the year 2015 was done and analysed using WHONET and SPSS. RESULTS:Analysis of 624 isolates revealed AMR rates higher than most recent local and international reports. 88% of isolates tested were multi-drug resistant (MDR) whereas 26% were extensively-drug resistant (XDR). E. coli and K. pneumoniae had poor susceptibility to penicillins (8-48%), cephalosporins (16-43%), monobactams (17-29%), fluoroquinolones (22-44%) and trimethoprim-sulfamethoxazole (7%). Pseudomonas aeruginosa and Acinetobacter baumanii were resistant to penicillins and cephalosporins, with reduced susceptibility to carbapenems (70% and 27% respectively). S aureus had poor susceptibility to penicillins (3%) and trimethoprim-sulfamethoxazole (29%) but showed excellent susceptibility to imipenem (90%), vancomycin (97%) and linezolid (99%). CONCLUSIONS:The overwhelming resistance to commonly used antibiotics heralds a clarion call towards strengthening antimicrobial stewardship programmes and regular AMR regional surveillance.
| S-EPMC6370290 | biostudies-literature
Project description:Brucellosis is a rarely encountered infection in Norway. The aim of this study was to explore all Brucella melitensis isolates collected in Norway from 1999 to 2016 in relation to origin of infection and antimicrobial resistance patterns. A total of 23 isolates were analysed by whole-genome sequencing and compared with selected sequences of B. melitensis available from NCBI. Additionally, SNP analysis in antibiotic resistance determining genes was performed. The majority belonged to the East Mediterranean clade (genotype II), while the remaining isolates belonged to the African clade (genotype III). These results indicate that human brucellosis in Norway is related to travels or migration from the Middle East, Asia or Africa, in accordance with results from Germany, Denmark and Sweden. Antibiotic susceptibility patterns were determined by broth microdilution method and/or gradient strip method. All isolates were susceptible for all tested antibiotics, except for rifampicin where phenotypical results indicated resistance or intermediate resistance in all isolates based on broth microdilution method, and in four isolates based on gradient strip testing. In contrast, screening of the rpoB gene did not reveal any mutations in the previously described rpoB "hot spot" regions related to rifampicin resistance, indicating overestimation of resistance based on phenotypical results.
| S-EPMC5986768 | biostudies-literature
Project description:BackgroundThe overuse of antimicrobials in food animals and the subsequent contamination of the environment have been associated with development and spread of antimicrobial resistance. This review presents information on antimicrobial use, resistance and status of surveillance systems in food animals and the environment in Africa.MethodsInformation was searched through PubMed, Google Scholar, Web of Science, and African Journal Online databases. Full-length original research and review articles on antimicrobial use, prevalence of AMR from Africa covering a period from 2005 to 2018 were examined. The articles were scrutinized to extract information on the antimicrobial use, resistance and surveillance systems.ResultsA total of 200 articles were recovered. Of these, 176 studies were included in the review while 24 articles were excluded because they were not relevant to antimicrobial use and/or resistance in food animals and the environment. The percentage of farms using antimicrobials in animal production ranged from 77.6% in Nigeria to 100% in Tanzania, Cameroon, Zambia, Ghana and Egypt. The most antibiotics used were tetracycline, aminoglycoside and penicillin groups. The percentage of multi drug resistant isolates ranged from 20% in Nigeria to 100% in South Africa, Zimbabwe and Tunisia. In the environment, percentage of multi drug resistant isolates ranged from 33.3% in South Africa to 100% in Algeria. None of the countries documented national antimicrobial use and resistance surveillance system in animals.ConclusionThere is high level of antimicrobial use, especially tetracycline, aminoglycoside and penicillin in animal production systems in Africa. This is likely to escalate the already high prevalence of antimicrobial resistance and multi drug resistance in the continent. This, coupled with weak antimicrobial resistance surveillance systems in the region is a great concern to the animals, environment and humans as well.
| S-EPMC7053060 | biostudies-literature
Project description:Microbial pathogens represent an increasing threat to human health. Although many infections can be successfully treated and cleared, drug resistance is a widespread problem. The existence of subpopulations of 'tolerant' cells (where a fraction of the population is able to grow above the population resistance level) may increase the rate of treatment failure; yet, existing methods to measure subpopulation effects are cumbersome. Here we describe diskImageR, a computational pipeline that analyses photographs of disk diffusion assays to determine the degree of drug susceptibility [the radius of inhibition, (RAD)], and two aspects of subpopulation growth [the fraction of growth (FoG) within the zone of inhibition, (ZOI), and the rate of change in growth from no drug to inhibitory drug concentrations, (SLOPE)]. diskImageR was used to examine the response of the human fungal pathogen Candida albicans to the antifungal drug fluconazole across different strain backgrounds and growth conditions. Disk diffusion assays performed under Clinical and Laboratory Standards Institute (CLSI) conditions led to more susceptibility and less tolerance than assays performed using rich medium conditions. We also used diskImageR to quantify the effects of three drugs in combination with fluconazole, finding that all three combinations affected tolerance, with the effect of one drug (doxycycline) being very strain dependent. The three drugs had different effects on susceptibility, with doxycycline generally having no effect, chloroquine generally increasing susceptibility and pyrvinium pamoate generally reducing susceptibility. The ability to simultaneously quantitate different aspects of microbial drug responses will facilitate the study of mechanisms of subpopulation responses in the presence of antimicrobial drugs.
| S-EPMC5756480 | biostudies-literature