Computational Analysis of the Molecular Mechanism of RamR Mutations Contributing to Antimicrobial Resistance in Salmonella enterica

Liu, Yen‐Yi; Chen, Chih-Chieh

doi:10.1038/s41598-017-14008-5

Cited by 7 publications

(4 citation statements)

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“…Certain mutations in ramR, such as those detected here (i. e. Y59H, M84I, E160D), affect the DNA binding affinity of RamR and reduce the repression of the ramA gene. This disruption leads to overexpression of ramA, which activates the major efflux-mediated AMR mechanism in Gram-negative bacteria: the acrAB-tolC RND multidrug efflux pump [53,54]. This feature is a broad-spectrum efflux system that confers resistance to unrelated antibiotic classes such as tetracyclines, quinolones, phenicols and beta-lactams [55].…”

Section: Discussionmentioning

confidence: 99%

Genomic surveillance of antimicrobial resistance shows cattle and poultry are a moderate source of multi-drug resistant non-typhoidal Salmonella in Mexico

et al. 2021

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Multi-drug resistant (MDR) non-typhoidal Salmonella (NTS) is a public health concern globally. This study reports the phenotypic and genotypic antimicrobial resistance (AMR) profiles of NTS isolates from bovine lymph nodes (n = 48) and ground beef (n = 29). Furthermore, we compared genotypic AMR data of our isolates with those of publicly available NTS genomes from Mexico (n = 2400). The probability of finding MDR isolates was higher in ground beef than in lymph nodes:χ2 = 12.0, P = 0.0005. The most common resistant phenotypes involved tetracycline (40.3%), carbenicillin (26.0%), amoxicillin-clavulanic acid (20.8%), chloramphenicol (19.5%) and trimethoprim-sulfamethoxazole (16.9%), while more than 55% of the isolates showed decreased susceptibility to ciprofloxacin and 26% were MDR. Conversely, resistance to cephalosporins and carbapenems was infrequent (0–9%). MDR phenotypes were strongly associated with NTS serovar (χ2 = 24.5, P<0.0001), with Typhimurium accounting for 40% of MDR strains. Most of these (9/10), carried Salmonella genomic island 1, which harbors a class-1 integron with multiple AMR genes (aadA2, blaCARB-2, floR, sul1, tetG) that confer a penta-resistant phenotype. MDR phenotypes were also associated with mutations in the ramR gene (χ2 = 17.7, P<0.0001). Among public NTS isolates from Mexico, those from cattle and poultry had the highest proportion of MDR genotypes. Our results suggest that attaining significant improvements in AMR meat safety requires the identification and removal (or treatment) of product harboring MDR NTS, instead of screening for Salmonella spp. or for isolates showing resistance to individual antibiotics. In that sense, massive integration of whole genome sequencing (WGS) technologies in AMR surveillance provides the shortest path to accomplish these goals.

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Section: Discussionmentioning

confidence: 99%

Genomic surveillance of antimicrobial resistance shows cattle and poultry are a moderate source of multi-drug resistant non-typhoidal Salmonella in Mexico

et al. 2021

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“…In addition, computational analyses have indicated that mutations in the dimerization domain of RamR can lead to a reduction in its DNA binding affinity in Salmonella spp. 55 . In our study, mutations in RamR were detected in both DNA binding and dimerization domains but mostly were point mutations that occurred outside hotspot regions.…”

Section: Discussionmentioning

confidence: 99%

Occurrence and mechanisms of tigecycline resistance in carbapenem- and colistin-resistant Klebsiella pneumoniae in Thailand

Chirabhundhu,

Luk-In,

Phuadraksa

et al. 2024

Sci Rep

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Tigecycline has been regarded as one of the most important last-resort antibiotics for the treatment of infections caused by extensively drug-resistant (XDR) bacteria, particularly carbapenem- and colistin-resistant Klebsiella pneumoniae (C-C-RKP). However, reports on tigecycline resistance have been growing. Overall, ~ 4000 K. pneumoniae clinical isolates were collected over a five-year period (2017–2021), in which 240 isolates of C-C-RKP were investigated. Most of these isolates (91.7%) were resistant to tigecycline. Notably, a high-risk clone of ST16 was predominantly identified, which was associated with the co-harboring of blaNDM-1 and blaOXA-232 genes. Their major mechanism of tigecycline resistance was the overexpression of efflux pump acrB gene and its regulator RamA, which was caused by mutations in RamR (M184V, Y59C, I141T, A28T, C99/C100 insertion), in RamR binding site (PI) of ramA gene (C139T), in MarR (S82G), and/or in AcrR (L154R, R13Q). Interestingly, four isolates of ST147 carried the mutated tet(A) efflux pump gene. To our knowledge, this is the first report on the prevalence and mechanisms of tigecycline resistance in C-C-RKP isolated from Thailand. The high incidence of tigecycline resistance observed among C-C-RKP in this study reflects an ongoing evolution of XDR bacteria against the last-resort antibiotics, which demands urgent action.

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“…RamR is the repressor of RamA and several mutations were identified in its dimerization domain, resulting in a decrease of DNA-binding affinity on the promoter of ramA in Salmonella [ 78 ]. It recognizes multiple chemicals such as bile components, crystal violet, ethidium bromide, rhodamine G, and the resulting association reduces its proper affinity for DNA target sites [ 79 ].…”

Section: Regulators Type 1—helix-turn-helix (Hth) Family Regulatormentioning

confidence: 99%

An Intertwined Network of Regulation Controls Membrane Permeability Including Drug Influx and Efflux in Enterobacteriaceae

et al. 2020

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The transport of small molecules across membranes is a pivotal step for controlling the drug concentration into the bacterial cell and it efficiently contributes to the antibiotic susceptibility in Enterobacteriaceae. Two types of membrane transports, passive and active, usually represented by porins and efflux pumps, are involved in this process. Importantly, the expression of these transporters and channels are modulated by an armamentarium of tangled regulatory systems. Among them, Helix-turn-Helix (HTH) family regulators (including the AraC/XylS family) and the two-component systems (TCS) play a key role in bacterial adaptation to environmental stresses and can manage a decrease of porin expression associated with an increase of efflux transporters expression. In the present review, we highlight some recent genetic and functional studies that have substantially contributed to our better understanding of the sophisticated mechanisms controlling the transport of small solutes (antibiotics) across the membrane of Enterobacteriaceae. This information is discussed, taking into account the worrying context of clinical antibiotic resistance and fitness of bacterial pathogens. The localization and relevance of mutations identified in the respective regulation cascades in clinical resistant strains are discussed. The possible way to bypass the membrane/transport barriers is described in the perspective of developing new therapeutic targets to combat bacterial resistance.

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Computational Analysis of the Molecular Mechanism of RamR Mutations Contributing to Antimicrobial Resistance in Salmonella enterica

Cited by 7 publications

References 50 publications

Genomic surveillance of antimicrobial resistance shows cattle and poultry are a moderate source of multi-drug resistant non-typhoidal Salmonella in Mexico

Genomic surveillance of antimicrobial resistance shows cattle and poultry are a moderate source of multi-drug resistant non-typhoidal Salmonella in Mexico

Occurrence and mechanisms of tigecycline resistance in carbapenem- and colistin-resistant Klebsiella pneumoniae in Thailand

An Intertwined Network of Regulation Controls Membrane Permeability Including Drug Influx and Efflux in Enterobacteriaceae

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