In silico genetic correlations of multidrug efflux pump gene expression in Staphylococcus aureus

Kosmidis, Chris; DeMarco, Carmen E.; Frempong-Manso, Emmanuel; Seo, Susan M.; Kaatz, Glenn W.

doi:10.1016/j.ijantimicag.2010.05.015

Cited by 12 publications

(11 citation statements)

References 44 publications

(49 reference statements)

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“…The pattern of gene expression encountered in this study showed some differences from the one found by DeMarco et al , the most striking being the absence of norA overexpression [105]. A different MDR pumps expression pattern was also reported for S. aureus prototype strains [84]. Altogether, these studies reveal that S. aureus clinical isolates may diverge in the efflux-mediated response to noxious agents, including fluoroquinolones, even when highly clonally related [105].…”

Section: Efflux-mediated Fluoroquinolone Resistancesupporting

confidence: 47%

“…SarZ, a MgrA homologue involved in the oxidative stress response of S. aureus was previously shown to downregulate norB and tet38 expression [83]. It has been documented that NorG is absent from some prototype S. aureus strains, such as MW2, MSSA476 and MRSA 252, showing that NorG may not be essential for efflux pump regulation in these strains [84]. …”

Section: Regulation Of S Aureus Mdr Efflux Pumpsmentioning

confidence: 99%

“…This molecule can be used as a marker for the indirect assessment of efflux activity, namely, by determination of ethidium bromide MICs to identify S. aureus strains that show increased efflux activity [84,104] in the presence/absence of efflux inhibitors [22,105], by the Ethidium Bromide-Agar Cartwheel Method, which evaluates the cells capacity to retain/extrude ethidium bromide after overnight incubation [106] or in assays that evaluate directly the efflux activity, using real-time fluorometry [107]. …”

Section: Assessing Efflux Activitymentioning

confidence: 99%

See 2 more Smart Citations

Multidrug Efflux Pumps in Staphylococcus aureus: an Update

Costa¹,

Viveiros²,

Amaral³

et al. 2013

TOMICROJ

315

290

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The emergence of infections caused by multi- or pan-resistant bacteria in the hospital or in the community settings is an increasing health concern. Albeit there is no single resistance mechanism behind multiresistance, multidrug efflux pumps, proteins that cells use to detoxify from noxious compounds, seem to play a key role in the emergence of these multidrug resistant (MDR) bacteria. During the last decades, experimental data has established their contribution to low level resistance to antimicrobials in bacteria and their potential role in the appearance of MDR phenotypes, by the extrusion of multiple, unrelated compounds. Recent studies suggest that efflux pumps may be used by the cell as a first-line defense mechanism, avoiding the drug to reach lethal concentrations, until a stable, more efficient alteration occurs, that allows survival in the presence of that agent. In this paper we review the current knowledge on MDR efflux pumps and their intricate regulatory network in Staphylococcus aureus, a major pathogen, responsible from mild to life-threatening infections. Particular emphasis will be given to the potential role that S. aureus MDR efflux pumps, either chromosomal or plasmid-encoded, have on resistance towards different antimicrobial agents and on the selection of drug - resistant strains. We will also discuss the many questions that still remain on the role of each specific efflux pump and the need to establish appropriate methodological approaches to address all these questions.

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Section: Efflux-mediated Fluoroquinolone Resistancesupporting

confidence: 47%

Section: Regulation Of S Aureus Mdr Efflux Pumpsmentioning

confidence: 99%

Section: Assessing Efflux Activitymentioning

confidence: 99%

See 1 more Smart Citation

Multidrug Efflux Pumps in Staphylococcus aureus: an Update

Costa¹,

Viveiros²,

Amaral³

et al. 2013

TOMICROJ

315

290

View full text Add to dashboard Cite

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“…Cooperative binding of MepR dimers to each signature motif in the mepA operator may be the basis for both the greater affinity and easier substrate induction at this site, perhaps in a manner similar to the interaction of QacR with the qacA operator (9). Using quantitative reverse transcription-PCR (qRT-PCR) we have identified numerous clinical and laboratory strains of S. aureus that overexpress mepA (6,(10)(11)(12)(13)(14). Understanding the mechanism(s) of mepA overexpression may provide clues for the design of means to overcome its potential deleterious clinical consequences.…”

mentioning

confidence: 99%

Functional Consequences of Substitution Mutations in MepR, a Repressor of the Staphylococcus aureus mepA Multidrug Efflux Pump Gene

et al. 2013

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The expression of mepA, encoding the Staphylococcus aureus MepA multidrug efflux protein, is repressed by the MarR homologue MepR. MepR dimers bind differently to operators upstream of mepR and mepA, with affinity being greatest at the mepA operator. MepR substitution mutations may result in mepA overexpression, with A103V most common in clinical strains. Evaluation of the functional consequences of this and other MepR substitutions using a lacZ reporter gene assay revealed markedly reduced repressor activity in the presence of Q18P, F27L, G97E, and A103V substitutions. Reporter data were generally supported by susceptibility and efflux assays, and electrophoretic mobility shift assays (EMSAs) confirmed compromised affinities of MepR F27L and A103V for the mepR and mepA operators. One mutant protein contained two substitutions (T94P and T132M); T132M compensated for the functional defect incurred by T94P and also rescued that of A103V but not F27L, establishing it as a limited-range suppressor. The function of another derivative with 10 substitutions was minimally affected, and this may be an extreme example of suppression involving interactions among several residues. Structural correlations for the observed functional effects were ascertained by modeling mutations onto apo-MepR. It is likely that F27L and A103V affect the protein-DNA interaction by repositioning of DNA recognition helices. Negative functional consequences of MepR substitution mutations may result from interference with structural plasticity, alteration of helical arrangements, reduced protein-cognate DNA affinity, or possibly association of MepR protomers. Structural determinations will provide further insight into the consequences of these and other mutations that affect MepR function, especially the T132M suppressor.

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“…We also showed that augmented expression was present in a small number of geographically and temporally diverse clinical S. aureus strains, indicating that this phenotype has existed for decades [6]. Whether or not these data can be generalised to contemporary strains from various geographic locales is unknown.…”

Section: Introductionmentioning

confidence: 81%