Clonal relatedness is a predictor of spontaneous multidrug efflux pump gene overexpression in Staphylococcus aureus

Schindler, Bryan D.; Jacinto, Pauline; Buensalido, Joseph Adrian L.; Seo, Susan M.; Kaatz, Glenn W.

doi:10.1016/j.ijantimicag.2014.11.007

Cited by 8 publications

(3 citation statements)

References 26 publications

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“…3 – 5 ). This dissimilar behavior is particularly striking as these are very closely related strains, as demonstrated by PFGE analysis and illustrates the multiple efflux-mediated responses that S. aureus can display within the same lineage, a finding in contrast to results from other studies [ 33 ]. Regarding the response to CIP, both strains (already carrying QRDR mutations conferring high-level resistance) showed mild values of EP gene overexpression, which may account for the additional level of resistance attributed to efflux.…”

Section: Discussioncontrasting

confidence: 75%

Impact of efflux in the development of multidrug resistance phenotypes in Staphylococcus aureus

et al. 2015

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BackgroundEfflux has been recognized as a resistance mechanism to antimicrobials in Staphylococcus aureus; however its role on the development of clinically relevant resistance is still poorly characterized. This study aimed to examine the impact of efflux on development of resistance to fluoroquinolones and other antimicrobials in S. aureus strains representing relevant phenotypes in terms of antibiotic susceptibility and efflux activity.MethodsTwo closely related methicillin- and ciprofloxacin-resistant Staphylococcus aureus clinical strains, with different efflux capacity and the pan-susceptible strain ATCC25923 were exposed to constant concentrations of the efflux pump (EP) substrates ciprofloxacin, ethidium bromide and cetrimide. Parental and exposed strains were tested regarding their susceptibility towards antibiotics, biocides and ethidium bromide, efflux capacity and levels of EP gene expression. Occurrence of resistance-associated mutations was screened by sequencing.ResultsMultidrug resistance phenotypes emerged upon exposure, independently of the substrate or its concentration, which were correlated with increased efflux capacity of the exposed strains. The temporal pattern of EP gene expression disclosed an early-response with high expression of several genes, followed by a late-response, characterized by overexpression of specific genes. The overall cell response was more pronounced for strains with an initial basal efflux activity. Remarkably, detection of the IS256 element in the promoter regions of mgrA and norA, in some cases associated with increased gene expression, suggests that these genes may be hot spots for IS256 insertion events.The results obtained with exposure of ATCC25923 to ciprofloxacin were particularly striking, revealing a step-wise development of fluoroquinolone resistance, with a first efflux-mediated response, followed by the occurrence of a mutation in grlA that resulted in phenotypic resistance. Additionally, challenge by non-fluoroquinolone agents, particularly cetrimide, promoted cross resistance to fluoroquinolones, revealing the potential role of biocides as selective pressure for the emergence of resistance to these antibiotics.ConclusionsThis study reveals efflux as a significant component of S. aureus resistance to fluoroquinolones and biocides and as a primary mechanism to withstand stress imposed by antimicrobials. This efflux-mediated response can result in the emergence of multidrug resistance in healthcare environments and should be taken into account in the management of this major pathogen.Electronic supplementary materialThe online version of this article (doi:10.1186/s12866-015-0572-8) contains supplementary material, which is available to authorized users.

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Section: Discussioncontrasting

confidence: 75%

Impact of efflux in the development of multidrug resistance phenotypes in Staphylococcus aureus

et al. 2015

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“…To date, more than twenty putative efflux pumps have been identified in the S. aureus genome but few have been characterized. Overexpression of these pumps is proposed to contribute to antibiotic resistance and possibly enhances survival in different environments (Santos Costa et al, 2013;Schindler et al, 2015;Jang, 2016;Sapula and Brown, 2016).…”

Section: Introductionmentioning

confidence: 99%

Evidence of Calcium Signaling and Modulation of the LmrS Multidrug Resistant Efflux Pump Activity by Ca2 + Ions in S. aureus

et al. 2020

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Calcium ions (Ca 2+) play a pivotal role in eukaryote cell signaling and regulate many physiological functions. Although a similar role for Ca 2+ in prokaryotes has been difficult to demonstrate, there is increasing evidence for Ca 2+ as a cell regulator in bacteria. The purpose of this study was to investigate Ca 2+ signaling and the effect of Ca 2+ on the Staphylococcus aureus multidrug resistant efflux pump LmrS. We hypothesized that antibiotics act by increasing Ca 2+ concentrations, which in turn enhance the efflux activity of LmrS. These Ca 2+ transients were measured by luminometry in response to various antibiotics by using the photoprotein aequorin reconstituted within live bacterial cells. Efflux associated with LmrS was measured by the increase in fluorescence due to the loss of ethidium bromide (EtBr) from both S. aureus cells and from E. coli cells in which the lmrs gene of S. aureus was expressed. We found that addition of antibiotics to cells generated unique cytosolic Ca 2+ transients and that addition of CaCl 2 to cells enhanced EtBr efflux whereas addition of Ca 2+ chelators or efflux pump inhibitors significantly decreased EtBr efflux from cells. We conclude that antibiotics induce a Ca 2+ mediated response through transients in cytosolic Ca 2+ , which then stimulates LmrS efflux pump.

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“…Meanwhile, G-Rh2 is one of the active compounds extracted from ginseng, exhibiting unique immune enhancement effect different from other efflux pump inhibitors (Lee et al, 2018). It is reported that exposure to a given antibiotic can induce the bacterium cell to synthesize more efflux pump units, thus adding additional survival advantage to the cell (Schindler et al, 2015;Foster, 2017;Willers et al, 2017). Therefore, inhibiting the efflux pumps in bacteria before their exposure to antibiotics may be a reasonable strategy to maximize the antibacterial effect, which inhibits antibiotic ejection in early stage, further increases intracellular concentrations of antibiotics, and enhances susceptibility of bacteria.…”

Section: Introductionmentioning

confidence: 99%

PLGA microsphere-based composite hydrogel for dual delivery of ciprofloxacin and ginsenoside Rh2 to treat Staphylococcus aureus -induced skin infections

et al. 2020

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When antibiotic-resistant pathogenic bacteria pose a high threat to human health, bacterial multidrug efflux pumps become major contributors to the high-level antibiotic resistance in most microorganisms. Since traditional antibiotics are still indispensable currently, we report a dual drug delivery system to maximize the antibacterial efficacy of antibiotics by inhibiting efflux pumps in bacteria before their exposure to antibiotics. In this research, a microsphere/hydrogel composite was constructed from ciprofloxacin (Cip)-loaded poly (lactic-co-glycolic acid) (PLGA) microspheres and ginsenoside Rh2 (G-Rh2) dispersed thermo-sensitive hydrogel to treat skin infections. In vitro drug release studies indicated that while G-Rh2 in hydrogel presented a faster and short-term release manner to rapidly inhibit the NorA efflux pumps, Cip showed a sustained and long-term release behavior to provide a local high concentration gradient for facilitating drug percutaneous penetration. The combination of Cip and G-Rh2 demonstrated a high degree of synergism against both methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA), hence significantly improving their in vitro antibacterial activity and efficiency. Moreover, the antibacterial performance of the microsphere/hydrogel composite with a sequential release profile is superior to that of other formulations in mouse model of MRSA skin infections, indicating its great potential to treat antibiotic-resistant skin infections.

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Clonal relatedness is a predictor of spontaneous multidrug efflux pump gene overexpression in Staphylococcus aureus

Cited by 8 publications

References 26 publications

Impact of efflux in the development of multidrug resistance phenotypes in Staphylococcus aureus

Impact of efflux in the development of multidrug resistance phenotypes in Staphylococcus aureus

Evidence of Calcium Signaling and Modulation of the LmrS Multidrug Resistant Efflux Pump Activity by Ca2 + Ions in S. aureus

PLGA microsphere-based composite hydrogel for dual delivery of ciprofloxacin and ginsenoside Rh2 to treat Staphylococcus aureus -induced skin infections

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