Mutations in the MepRAB efflux system contribute to the in vitro development of tigecycline resistance in Staphylococcus aureus

Fang, Ru; Sun, Yao; Dai, Weisi; Zheng, Xiangkuo; Tian, Xuebin; Zhang, Xiucai; Wang, Chong; Cao, Jianming; Zhou, Tieli

doi:10.1016/j.jgar.2020.06.005

Cited by 7 publications

(6 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We also detected different mutation sites (such as M1L and Y58D) in S10 in the tetracyclines-resistant isolates. K57M was found in both tetracyclines-resistant and-susceptible strains, suggesting that it was not associated with tetracyclines resistance (Fang et al, 2020). Consistent with the findings of Wang et al (Wang et al, 2020), no mutations were detected in the 30S ribosome protein S3, illustrating that S3 was not the predominant factor contributing to tetracyclines resistance in S. aureus.…”

Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

“…Another important resistance mechanism is the active efflux pump. The MepRAB efflux pump, a novel MATE family efflux pump, plays a key role in tigecycline resistance in S. aureus ( McAleese et al, 2005 ; Fang et al, 2020 ), however, whether it affects eravacycline and omadacycline resistance is unclear. We first analyzed ta mutation in MepRAB efflux pump-encoding genes.…”

Section: Discussionmentioning

confidence: 99%

“…Overexpression of efflux pumps has been reported both in Gram-positive and Gram-negative pathogens ( Truong-Bolduc et al, 2015 ; Fiedler et al, 2016 ; Zhanel et al, 2016 ). Mutations or overexpression of the MepRAB efflux pump contributes to the decreased susceptibility to tigecycline ( McAleese et al, 2005 ; Fang et al, 2020 ). Recent studies have revealed that a branched-chain amino acid transport system II carrier protein affects eravacycline and omadacycline susceptibility in S. aureus ( Bai et al, 2019 ; Wang et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

In vitro antimicrobial activity and resistance mechanisms of the new generation tetracycline agents, eravacycline, omadacycline, and tigecycline against clinical Staphylococcus aureus isolates

et al. 2022

Self Cite

View full text Add to dashboard Cite

In this study, we investigated the in vitro activity and resistance mechanisms of the new generation tetracycline agents, namely eravacycline, omadacycline, and tigecycline, against Staphylococcus aureus isolates. A total of 1,017 non-duplicate S. aureus isolates were collected and subjected to susceptibility testing against eravacycline, omadacycline, and tigecycline using the broth microdilution method. Tetracyclines-resistant (eravacycline/omadacycline/tigecycline-resistant) isolates were selected to elucidate the resistance mechanisms using polymerase chain reaction (PCR), cloning experiment, efflux pump inhibition, and quantitative real-time PCR. The results of the antibacterial susceptibility testing showed that compared with omadacycline, eravacycline and tigecycline had superior antibacterial activity against S. aureus isolates. Among 1,017 S. aureus, 41 tetracyclines-resistant isolates were identified. These resistant isolates possessed at least one tetracycline resistance gene and genetic mutation in the MepRAB efflux pump and 30S ribosome units. A frameshift mutation in mepB was detected in most tetracyclines-resistant strains (except for JP3349) compared with tetracyclines-susceptible (eravacycline/omadacycline/tigecycline-susceptible) strains. This was first shown to decrease susceptibility to omadacycline, but not to eravacycline and tigecycline. After treatment with eravacycline, omadacycline or tigecycline, overexpression of mepA, tet38, tet(K) and tet(L) was detected. Moreover, multi-locus sequence typing showed a major clonal dissemination type, ST5, and its variant ST764 were seen in most tetracyclines-resistant strains. To conclude, eravacycline and tigecycline exhibited better activity against S. aureus including tetracycline-resistant isolates than omadacycline. The resistance to these new generation tetracyclines due to an accumulation of many resistance mechanisms.

show abstract

Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

In vitro antimicrobial activity and resistance mechanisms of the new generation tetracycline agents, eravacycline, omadacycline, and tigecycline against clinical Staphylococcus aureus isolates

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…MepA (451 amino acids) has 12 TMS and presents 21% amino acid identity to the MATE transporter NorM from Vibrio parahaemolyticus [ 27 , 113 , 160 ]. MepA is associated with a MDR phenotype in clinical S. aureus isolates, mediating low-level resistance to several monovalent and bivalent biocides and dyes [ 161 ], as well as to tigecycline [ 162 ], a glycylcycline antibiotic. Like the MFS transporter NorA, MepA is an important fluoroquinolone efflux system in S. aureus that expels hydrophilic fluoroquinolone antibiotics such as norfloxacin and ciprofloxacin.…”

Section: Prototypical Characterised Efflux Pumps In Staphylococcimentioning

confidence: 99%

Efflux Pump Mediated Antimicrobial Resistance by Staphylococci in Health-Related Environments: Challenges and the Quest for Inhibition

Dashtbani-Roozbehani

Brown

2021

Antibiotics

View full text Add to dashboard Cite

The increasing emergence of antimicrobial resistance in staphylococcal bacteria is a major health threat worldwide due to significant morbidity and mortality resulting from their associated hospital- or community-acquired infections. Dramatic decrease in the discovery of new antibiotics from the pharmaceutical industry coupled with increased use of sanitisers and disinfectants due to the ongoing COVID-19 pandemic can further aggravate the problem of antimicrobial resistance. Staphylococci utilise multiple mechanisms to circumvent the effects of antimicrobials. One of these resistance mechanisms is the export of antimicrobial agents through the activity of membrane-embedded multidrug efflux pump proteins. The use of efflux pump inhibitors in combination with currently approved antimicrobials is a promising strategy to potentiate their clinical efficacy against resistant strains of staphylococci, and simultaneously reduce the selection of resistant mutants. This review presents an overview of the current knowledge of staphylococcal efflux pumps, discusses their clinical impact, and summarises compounds found in the last decade from plant and synthetic origin that have the potential to be used as adjuvants to antibiotic therapy against multidrug resistant staphylococci. Critically, future high-resolution structures of staphylococcal efflux pumps could aid in design and development of safer, more target-specific and highly potent efflux pump inhibitors to progress into clinical use.

show abstract

In vitro activity of tigecycline and proteomic analysis of tigecycline adaptation strategies in clinical Enterococcus faecalis isolates from China

Bai

Chen

Zhao

et al. 2022

Journal of Global Antimicrobial Resistance

View full text Add to dashboard Cite

Mutations in the MepRAB efflux system contribute to the in vitro development of tigecycline resistance in Staphylococcus aureus

Cited by 7 publications

References 27 publications

In vitro antimicrobial activity and resistance mechanisms of the new generation tetracycline agents, eravacycline, omadacycline, and tigecycline against clinical Staphylococcus aureus isolates

In vitro antimicrobial activity and resistance mechanisms of the new generation tetracycline agents, eravacycline, omadacycline, and tigecycline against clinical Staphylococcus aureus isolates

Efflux Pump Mediated Antimicrobial Resistance by Staphylococci in Health-Related Environments: Challenges and the Quest for Inhibition

In vitro activity of tigecycline and proteomic analysis of tigecycline adaptation strategies in clinical Enterococcus faecalis isolates from China

Contact Info

Product

Resources

About