Mutations at the Ribosomal S10 Gene in Clinical Strains of Staphylococcus aureus with Reduced Susceptibility to Tigecycline

Argudín, Maria Ángeles; Roisin, Sandrine; Dodémont, Magali; Nonhoff, Claire; Deplano, Ariane; Denis, Olivier

doi:10.1128/aac.01852-17

Cited by 12 publications

(14 citation statements)

References 9 publications

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“…A K57M amino acid substitution in the ribosomal S10 gene was detected in CP3_late genome. Remarkably, two clinical S. aureus isolates with mutation in this same region of the S10 protein (a deletion of residues 56 to 59; and double mutant K57M, Y58F) have been recently shown to confer resistance to tigecyclin [46].…”

Section: Resultsmentioning

confidence: 99%

Chronic Staphylococcus aureus lung infection correlates with proteogenomic and metabolic adaptations leading to an increased intracellular persistence

Tan

Coureuil

Ramond

et al. 2018

Preprint

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BackgroundChronic lung infection of cystic fibrosis (CF) patients by Staphylococcus aureus is a well-established epidemiological fact. Indeed, S. aureus is the most commonly identified pathogen in the lungs of CF patients. Strikingly the molecular mechanisms underlying S. aureus persistency are not understood.MethodsWe selected pairs of sequential S. aureus isolates from 3 patients with CF and from one patient with non-CF chronic lung disease. We used a combination of genomic, proteomic and metabolomic approaches with functional assays for in-depth characterization of S. aureus long-term persistence.ResultsFor the first time, we show that late S. aureus isolates from CF patients have an increased ability for intracellular survival in CFBE-F508del cells compared to ancestral early isolates. Importantly, the increased ability to persist intracellularly was confirmed for S. aureus isolates within the own patient F508del epithelial cells. An increased ability to form biofilm was also demonstrated.Furthermore, we identified the underlying genetic modifications inducing altered protein expression profiles and notable metabolic changes. These modifications affect several metabolic pathways and virulence regulators that could constitute therapeutic targets.ConclusionsOur results strongly suggest that the intracellular environment might constitute an important niche of persistence and relapse necessitating adapted antibiotic treatments.SummaryS. aureus persists for years in the lungs of patients with cystic fibrosis despite antibiotic therapies. We demonstrate that S. aureus adaptation leads to increased intracellular persistence suggesting a key role for intracellular niche during S. aureus chronic lung infection.

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Section: Resultsmentioning

confidence: 99%

Chronic Staphylococcus aureus lung infection correlates with proteogenomic and metabolic adaptations leading to an increased intracellular persistence

Tan

Coureuil

Ramond

et al. 2018

Preprint

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“…Recent crystallographic analysis studies have revealed the same mechanism of the new-generation tetracycline class antibiotics, including Tige, Omada and Erava, to inhibit bacterial protein synthesis by binding to the 30S ribosomal subunits, including 16SrRNA and 30S ribosome protein S10 [8,18]. Previous researches indicated that genetic mutations affecting the 30S ribosome subunits (i.e., 16SrRNA and ribosome proteins S10) have been shown to confer resistance to Tige and Omada in S. aureus [9][10][11][12][13][14][15][16][17]18]. However, the characteristics of genetic mutation of the 30S ribosome subunits and cross resistance in Erava resistant S. aureus remains unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Meanwhile, our study revealed high frequency of genetic mutations in 30S ribosome protein S10 in Erava-derived resistant isolates, indicating this protein might be an important factor in Erava resistance evolution. Previous multiple reports have shown that the mutation in 30S ribosome protein S10 of S. aureus can result in the MIC elevation of tetracycline, Omada and Tige, indicating its important role in the resistance evolution of tetracycline class drugs [6,9,12,13,15,17]. Therefore, the cross resistance under Erava pressure with Omada and Tige might be mainly explained by the genetic mutation of 30S ribosome subunits The frequent occurrence of antibiotics heteroresistance can result in the treatment failure.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous data indicated that tet(K) was frequently detected in MSSA with Erava MIC ≥0.5mg/L and it's still unknown whether tet(K) participated in the Erava heteroresistance or resistance [7]. The reduced susceptibility to Tige have been widely explained by the emergent mutations in genes encoding several 30S ribosome subunits, including 16S rRNA and 30S ribosome protein S10 [8][9][10][11][12][13][14][15][16][17]. The clinical significance of the genetic mutations of 30S ribosome subunits remains elusive should be further studied.…”

Section: Introductionmentioning

confidence: 99%

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Eravacycline susceptibility was impacted by genetic mutation of 30S ribosome subunits, and branched-chain amino acid transport system II carrier protein, Na/Pi cotransporter family protein in Staphylococcus aureus

Wang

Bai

et al. 2020

BMC Microbiol

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Background: Our previous research indicated the excellent in vitro antibacterial activity of Eravacycline (Erava) and its heteroresistance frequency against clinical Staphylococcus aureus isolates. In this study, we further aimed to investigate the mechanisms of Erava resistance and heteroresistance in S. aureus. Eight parental S. aureus isolates were induced under Erava pressure in vitro and the Erava-resistant isolates were selected and identified. Then, the genetic mutations of 30S ribosomal subunits were analyzed by PCR and sequence alignment. RT-qPCR analysis were performed to compare the relative expression of eight candidate genes impacting the susceptibility of tetracycline (Tet) between the resistant or heteroresistant and parental isolates. Furthermore, the in vitro overexpression vectors of three selected candidate genes were constructed to test their impact on the heteroresistance and resistance of Erava in S. aureus. Results: The MICs elevation in Erava-induced resistant S. aureus isolates were identified and the increasing MICs values of another two Tet class antibiotics, including both omadacycline (Omada) and tigecycline (Tige) were also tested. Genetic mutations in 30S ribosomal protein S10 were found frequently in Erava-derived resistant isolates. RT-qPCR analysis and the in vitro overexpression experiments indicated that USA300HOU_RS00550 (an Na/Pi cotransporter family protein) and USA300HOU_RS01625 (a branched-chain amino acid transport system II carrier protein) contributed to Erava heteroresistance in S. aureus.

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“…Tigecycline is the first semi-synthetic antibiotic under the minocycline antibiotic class. Studies have reported MRSA to have overexpression of efflux pump through the mutations of both mep R and mep A genes resulting in overexpression of mep A and derepression of mep R. Furthermore, studies have shown the mutation of the ribosomal protein at S10 (Argudín et al, 2018 ). Study by Dabul et al ( 2018 ) found out that mutation in rpsJ was not observed in their MRSA strain studied, but only the efflux mechanism was determined (Dabul et al, 2018 ).…”

Section: The Mechanisms Of Antibiotic Resistance In Mrsamentioning

confidence: 99%

Streptomyces as a Prominent Resource of Future Anti-MRSA Drugs

et al. 2018

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Methicillin-resistant Staphylococcus aureus (MRSA) pose a significant health threat as they tend to cause severe infections in vulnerable populations and are difficult to treat due to a limited range of effective antibiotics and also their ability to form biofilm. These organisms were once limited to hospital acquired infections but are now widely present in the community and even in animals. Furthermore, these organisms are constantly evolving to develop resistance to more antibiotics. This results in a need for new clinically useful antibiotics and one potential source are the Streptomyces which have already been the source of several anti-MRSA drugs including vancomycin. There remain large numbers of Streptomyces potentially undiscovered in underexplored regions such as mangrove, deserts, marine, and freshwater environments as well as endophytes. Organisms from these regions also face significant challenges to survival which often result in the production of novel bioactive compounds, several of which have already shown promise in drug development. We review the various mechanisms of antibiotic resistance in MRSA and all the known compounds isolated from Streptomyces with anti-MRSA activity with a focus on those from underexplored regions. The isolation of the full array of compounds Streptomyces are potentially capable of producing in the laboratory has proven a challenge, we also review techniques that have been used to overcome this obstacle including genetic cluster analysis. Additionally, we review the in vivo work done thus far with promising compounds of Streptomyces origin as well as the animal models that could be used for this work.

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Mutations at the Ribosomal S10 Gene in Clinical Strains of Staphylococcus aureus with Reduced Susceptibility to Tigecycline

Cited by 12 publications

References 9 publications

Chronic Staphylococcus aureus lung infection correlates with proteogenomic and metabolic adaptations leading to an increased intracellular persistence

Chronic Staphylococcus aureus lung infection correlates with proteogenomic and metabolic adaptations leading to an increased intracellular persistence

Eravacycline susceptibility was impacted by genetic mutation of 30S ribosome subunits, and branched-chain amino acid transport system II carrier protein, Na/Pi cotransporter family protein in Staphylococcus aureus

Streptomyces as a Prominent Resource of Future Anti-MRSA Drugs

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