An EmrB multidrug efflux pump in Burkholderia thailandensis with unexpected roles in antibiotic resistance

Sabrin, Afsana; Gioe, Brennan W.; Gupta, Ashish; Grove, Anne

doi:10.1074/jbc.ra118.006638

Cited by 12 publications

(10 citation statements)

References 38 publications

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“…In fact, in our study, a homolog of marR, a negative pump regulator, was down-regulated in persistent cells. In line with these data, increased resistance in Burkholderia thailandensis was attributed to enhanced e ux pump activity and was detected after repression of a marR homolog (Sabrin et al, 2019). Additionally, we found that a gene in the GntR family of regulators was also down-regulated in penicillin-persistent GAS cells.…”

Section: Discussionsupporting

confidence: 84%

Occurrence of antimicrobial persistence in Streptococcus pyogenes

Martini

Coronado

Melo

et al. 2021

Preprint

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Streptococcus pyogenes (group A Streptococcus-GAS) is an important pathogen for humans. GAS has been associated with severe and invasive diseases. Despite the fact that these bacteria remain universally susceptible to penicillin, therapeutic failures have been reported in some GAS infections. Many hypotheses have been proposed to explain these antibiotic-unresponsive infections, however none of them have fully elucidated this phenomenon. In this study, we show that GAS strains have the ability to form antimicrobial-persistent cells when growing on abiotic surfaces in a biofilm-like environment. Our data suggest that efflux activity was possibly involved in this phenomenon. In fact, gene expression assays by real-time qRT-PCR showed upregulation of some genes associated with efflux pumps in persistent cells arising in the presence of penicillin. Phenotypic reversion assay and whole-genome sequence analysis indicated that this event was due to non-inherited resistance mechanisms. The small persistent colonies showed downregulation of genes associated with protein biosynthesis and cell growth, as demonstrated by gene expression assays. Moreover, the proteomic analysis showed that susceptible cells express higher levels of ribosome proteins. It is conceivable to suppose that the generation of persistent cells by S. pyogenes might a mechanism of antimicrobial refractory during the course of real GAS invasive infections, which has been overlooked. Accordingly, the phenomenon described here might shed some light on the origin of therapeutic failures in S. pyogenes infections. Multifactorial mechanisms involving efflux pump activity, protein synthesis inhibition and cell-growth impairment seem to play roles in generation of GAS-persistent cells.

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Section: Discussionsupporting

confidence: 84%

Occurrence of antimicrobial persistence in Streptococcus pyogenes

Martini

Coronado

Melo

et al. 2021

Preprint

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“…In line with these data, increased resistance in Burkholderia thailandensis was attributed to enhanced e ux pump activity and was detected after repression of a marR homolog. 33 Additionally, we found that a gene in the GntR family of regulators was also down-regulated in penicillin-persistent GAS cells. It is remarkable that a norG knockout in S. aureus (a member of the GntR family) led to a 3-fold increase in the expression of an abcA gene encoding a protein of the ABC transport system with a concomitant increase in resistance to βlactams.…”

Section: Discussionmentioning

confidence: 80%

High Cell Density and Antimicrobial Persistence in Streptococcus Pyogenes 

Martini

Coronado

Melo

et al. 2020

Preprint

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Streptococcus pyogenes (group A Streptococcus-GAS) is an important pathogen for humans. GAS has been associated with severe and invasive diseases. Despite the fact that these bacteria remain universally susceptible to penicillin, therapeutic failures have been reported in some GAS infections. Many hypotheses have been proposed to explain these antibiotic-unresponsive infections, however none of them has fully elucidated this phenomenon. In this study, antimicrobial persistence emerged when GAS strains were grown at high cell density. Strong efflux activity was detected, and gene expression assays by real-time qRT-PCR showed upregulation of some genes associated with efflux pumps in persistent cells arising in the presence of penicillin. Subsequent phenotypic reversion and whole-genome sequencing indicated that this event was due to non-inherited resistance mechanisms. The tiny persistent colonies showed downregulation of genes associated with protein biosynthesis and cell growth, as demonstrated by gene expression assays. Moreover, proteomic analyses showed that susceptible cells express higher levels of ribosome proteins. The generation of persistent cells due to high bacterial load might be an important mechanism of clinical resistance in GAS invasive infections that has been overlooked. The phenomenon described here might shed some light on the origin of therapeutic failures in S. pyogenes infections.

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“…EmrB, the important integral protein of cell membranes, has been well-studied and identified as a multidrug efflux pump [ 31 , 32 ]. To further clarify the function of emrB in P3M, we constructed the deletion mutant strain ∆ emrB and complemented the com- emrB strain, and detected their survival phenotypes.…”

Section: Resultsmentioning

confidence: 99%

A Novel Non-Coding RNA CsiR Regulates the Ciprofloxacin Resistance in Proteus vulgaris by Interacting with emrB mRNA

Zhang

Song

Qin

et al. 2021

IJMS

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Bacterial non-coding RNAs (ncRNAs) play important regulatory roles in various physiological metabolic pathways. In this study, a novel ncRNA CsiR (ciprofloxacin stress-induced ncRNA) involved in the regulation of ciprofloxacin resistance in the foodborne multidrug-resistant Proteus vulgaris (P. vulgaris) strain P3M was identified. The survival rate of the CsiR-deficient strain was higher than that of the wild-type strain P3M under the ciprofloxacin treatment condition, indicating that CsiR played a negative regulatory role, and its target gene emrB was identified through further target prediction, quantitative real-time PCR (qRT-PCR), and microscale thermophoresis (MST). Further studies showed that the interaction between CsiR and emrB mRNA affected the stability of the latter at the post-transcriptional level to a large degree, and ultimately affected the ciprofloxacin resistance of P3M. Notably, the base-pairing sites between CsiR and emrB mRNAs were highly conserved in other sequenced P. vulgaris strains, suggesting that this regulatory mechanism may be ubiquitous in this species. To the best of our knowledge, this is the first identification of a novel ncRNA involved in the regulation of ciprofloxacin resistance in P. vulgaris species, which lays a solid foundation for comprehensively expounding the antibiotic resistance mechanism of P. vulgaris.

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An EmrB multidrug efflux pump in Burkholderia thailandensis with unexpected roles in antibiotic resistance

Cited by 12 publications

References 38 publications

Occurrence of antimicrobial persistence in Streptococcus pyogenes

Occurrence of antimicrobial persistence in Streptococcus pyogenes

High Cell Density and Antimicrobial Persistence in Streptococcus Pyogenes

A Novel Non-Coding RNA CsiR Regulates the Ciprofloxacin Resistance in Proteus vulgaris by Interacting with emrB mRNA

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An EmrB multidrug efflux pump in Burkholderia thailandensis with unexpected roles in antibiotic resistance

Cited by 12 publications

References 38 publications

Occurrence of antimicrobial persistence in Streptococcus pyogenes

Occurrence of antimicrobial persistence in Streptococcus pyogenes

High Cell Density and Antimicrobial Persistence in Streptococcus Pyogenes&nbsp;

A Novel Non-Coding RNA CsiR Regulates the Ciprofloxacin Resistance in Proteus vulgaris by Interacting with emrB mRNA

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High Cell Density and Antimicrobial Persistence in Streptococcus Pyogenes