Characterization of the DNA mismatch repair proteins MutS and MutL in a hypermutator Acinetobacter baumannii

Deihim, Behnaz; Hassanzadeh, Malihe; Shafiei-Jandaghi, Nazanin Zahra; Amanlou, Massoud; Douraghi, Masoumeh

doi:10.1016/j.micpath.2017.10.001

Cited by 3 publications

(3 citation statements)

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“…In addition to high mutation frequency, MMR deficiency is associated with antibiotic susceptibility in hypermutators, and the hypermutators exhibit higher antibiotic resistance than normal bacteria (LeClerc et al, 1996;Oliver et al, 2002;Wilson et al, 2014). In a clinical isolate of Acinetobacter baumannii, D278N substitution in the core domain of MutS was found to confer a hypermutable phenotype and strong multiantibiotic resistance (Deihim et al, 2017). Similar to the findings in A. baumannii, all Salmonella hypermutators examined in our current study were resistant to multiple antibiotics (Wang et al, 2015a,b;Yang et al, 2010Yang et al, , 2013.…”

Section: Discussionmentioning

confidence: 99%

Genes and Proteomes Associated With Increased Mutation Frequency and Multidrug Resistance of Naturally Occurring Mismatch Repair-Deficient Salmonella Hypermutators

et al. 2020

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The emergence of antibiotic-resistant Salmonella through mutations led to mismatch repair (MMR) deficiency that represents a potential hazard to public health. Here, four representative MMR-deficient Salmonella hypermutator strains and Salmonella Typhimurium LT2 were used to comprehensively reveal the influence of MMR deficiency on antibiotic resistance among Salmonella. Our results indicated that the mutation frequency ranged from 3.39 × 10 −4 to 5.46 × 10 −2 in the hypermutator. Mutation sites in MutS, MutL, MutT, and UvrD of the four hypermutators were all located in the essential and core functional regions. Mutation frequency of the hypermutator was most highly correlated with the extent of mutation in MutS. Mutations in MMR genes (mutS, mutT, mutL, and uvrD) were correlated with increased mutation in antibiotic resistance genes, and the extent of antibiotic resistance was significantly correlated with the number of mutation sites in MutL and in ParC. The number of mutation sites in MMR genes and antibiotic resistance genes exhibited a significant positive correlation with the number of antibiotics resisted and with expression levels of mutS, mutT, and mutL. Compared to Salmonella Typhimurium LT2, a total of 137 differentially expressed and 110 specifically expressed proteins were identified in the four hypermutators. Functional enrichment analysis indicated that the proteins significantly overexpressed in the hypermutators primarily associated with translation and stress response. Interaction network analysis revealed that the ribosome pathway might be a critical factor for high mutation frequency and multidrug resistance in MMR-deficient Salmonella hypermutators. These results help elucidate the mutational dynamics that lead to hypermutation, antibiotic resistance, and activation of stress response pathways in Salmonella.

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Section: Discussionmentioning

confidence: 99%

Genes and Proteomes Associated With Increased Mutation Frequency and Multidrug Resistance of Naturally Occurring Mismatch Repair-Deficient Salmonella Hypermutators

et al. 2020

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“…12 Mutations that inactivate mutS as well as mutL, encoding for a protein that provides stability for MutS during mismatch repair, are primarily frameshift point mutations that principally affect the C-terminus of MutS preventing ATP binding and hydrolysis, and the C-terminus of MutL inhibiting dimerization. 13 These point mutations, given their appreciable frequency in clinical isolates, would be difficult to prevent with therapeutics; therefore, it is important that any new therapies have low endogenous resistance potential. 13 , 14 While this may seem obvious, it is worth stressing that any target that can be altered quickly would limit the longevity of any new potential treatment.…”

Section: Gene Acquisition and Adaptationmentioning

confidence: 99%

Developing new therapeutic approaches for treating infections caused by multi-drug resistant Acinetobacter baumannii

Gallagher

Baker

2020

Journal of Infection

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Antimicrobial resistance (AMR) represents a major challenge to global health. This problem is most apparent in healthcare facilities, with a comparatively small number of pathogens being responsible for a substantial burden of hospital acquired infections globally. One of the key pathogens is the Gram-negative coccobacilli, Acinetobacter baumannii. It has been estimated that between 47% and 93% of A. baumannii infections are associated with multi-drug resistance (MDR), which is facilitated through a variety of well documented mechanisms (β-lactamases, efflux pumps, aminoglycoside-modifying enzymes, permeability defects, and target modifications). As our current pool of antimicrobial treatments becomes increasingly less effective, it is vital to identify new targets that can aid in the development novel treatments and strategies. In this we review we outline the key virulence mechanisms in A. baumannii (gene acquisition and adaptation, resistance to stresses, biofilm formation, and host interaction) and discuss their potential as targets for new therapeutics to reduce the impact of infections caused by MDR A. baumannii .

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“…Using this technique, it is possible to create enormous and diverse IL-2 mutein libraries that can, later on, be used as a selection method based on the desire ligand-receptor affinity 13 . There other several techniques used for the creation of new ligand mutants like protein-protein docking bioinformatics; or for creating different sets of libraries like MutS bacterial strains or error-prone PCR 14,15 .…”

Section: Il2 R α Regulationmentioning

confidence: 99%

Therapeutics and prospects of Interleukin 2

Lovato

Padilla

2019

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Interleukin-2 was discovered back in 1983 as an autocrine growth factor for cultured T cells and was the first biological product created through the use of recombinant DNA. IL-2 tumor immunotherapy performed the first historical clinical demonstration of the possibility to cause an effective anticancer immune reaction, mediated by cytotoxic lymphocytes activated from IL-2 stimulation. The Interleukin 2 receptor is a heterotrimeric protein that is composed of three peptide chains: the alpha chain, the beta chain and the gamma chain of the common cytokine receptor. There are 3 majors’ ways of interfering with the IL-2/IL-2R to use it as treatments: Antibodies, Aptamers, and punctual mutagenesis. Recent studies have shown, that Il-2 therapies for cancer, specifically targets restoring the individual’s natural antitumor immune response. HIV directed treatments have demonstrated the necessity of introducing the IL-2 complemented with the patient’s antiretroviral therapy.

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Characterization of the DNA mismatch repair proteins MutS and MutL in a hypermutator Acinetobacter baumannii

Cited by 3 publications

References 50 publications

Genes and Proteomes Associated With Increased Mutation Frequency and Multidrug Resistance of Naturally Occurring Mismatch Repair-Deficient Salmonella Hypermutators

Genes and Proteomes Associated With Increased Mutation Frequency and Multidrug Resistance of Naturally Occurring Mismatch Repair-Deficient Salmonella Hypermutators

Developing new therapeutic approaches for treating infections caused by multi-drug resistant Acinetobacter baumannii

Therapeutics and prospects of Interleukin 2

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