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Sub-Inhibitory Concentrations of Mupirocin Strongly Inhibit Alpha-Toxin Production in High-Level Mupirocin-Resistant MRSA by Down-Regulating agr, saeRS, and sarA.

ABSTRACT: Mupirocin, a topical antibiotic, has been utilized for decades to treat Staphylococcus aureus skin infections, as well as to decolonize patients at risk of methicillin-resistant S. aureus (MRSA) infection. The aims of this study were to investigate the expression of ?-toxin (encoded by the hla gene) in ten clinical MRSA strains (MIC = 1024 ?g/ml) in response to a sub-inhibitory concentration of mupirocin (1/32 minimum inhibitory concentration [MIC]) (32 ?g/ml) by using ?-toxin activity determination and enzyme-linked immune sorbent assay (ELISA). Subsequently, real-time polymerase chain reaction (RT-PCR) was used to examine the expression of saeR, agrA, RNAIII, and sarA genes under sub-inhibitory concentration of mupirocin in order to investigate the mechanism of action of this treatment regarding its strong inhibition of ?-toxin expression. For all the strains tested, mupirocin dramatically reduced mRNA levels of ?-toxin. The results indicated that ?-toxin activity in mupirocin-treated groups was significantly lower than that in untreated groups. The results show that the levels of agrA, RNAIII, saeR, and sarA expression significantly decrease by 11.82- to 2.23-fold (P < 0.01). Moreover, we speculate that mupirocin-induced inhibition of ?-toxin expression may be related to the inhibition of regulatory loci, such as agr, sarA and saeRS. More specifically, we found that the mechanism involves inhibiting the expression of agrA and RNAIII. In conclusion, sub-inhibitory concentrations of mupirocin strongly inhibit alpha-toxin production in high-level mupirocin-resistant MRSA by down-regulating agr, saeRS and sarA, which could potentially be developed as a supplemental treatment to control high-level mupirocin-resistant MRSA infection and reduce the risk of infection and colonization.

SUBMITTER: Jin Y

PROVIDER: S-EPMC5962727 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Sub-Inhibitory Concentrations of Mupirocin Strongly Inhibit Alpha-Toxin Production in High-Level Mupirocin-Resistant MRSA by Down-Regulating agr, saeRS, and sarA.

Jin Ye Y Li Meilan M Shang Yongpeng Y Liu Li L Shen Xiaofei X Lv Zhihui Z Hao Zhihao Z Duan Jingjing J Wu Yang Y Chen Chun C Pan Jingye J Yu Fangyou F

Frontiers in microbiology 20180515

Mupirocin, a topical antibiotic, has been utilized for decades to treat Staphylococcus aureus skin infections, as well as to decolonize patients at risk of methicillin-resistant S. aureus (MRSA) infection. The aims of this study were to investigate the expression of α-toxin (encoded by the hla gene) in ten clinical MRSA strains (MIC = 1024 μg/ml) in response to a sub-inhibitory concentration of mupirocin (1/32 minimum inhibitory concentration [MIC]) (32 μg/ml) by using α-tox ...[more]

PMID: 29867891

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Project description:Methicillin-resistant Staphylococcus aureus (MRSA) is a deleterious human pathogen responsible for severe morbidity and mortality worldwide. The pathogen has attained high priority in the World Health Organization (WHO) - Multidrug-resistant (MDR) pathogens list. Emerging MDR strains of S. aureus are clinically challenging due to failure in conventional antibiotic therapy. Biofilm formation is one of the underlying mechanisms behind the antibiotic resistance. Hence, attenuating biofilm formation has become an alternative strategy to control persistent infections. The current study is probably the first that focuses on the antibiofilm and antivirulence potential of myrtenol against MRSA and its clinical isolates. Myrtenol exhibited a concentration-dependent biofilm inhibition without causing any harmful effect on cell growth and viability. Further, microscopic analysis validated the biofilm inhibitory efficacy of myrtenol against MRSA. In addition, myrtenol inhibited the synthesis of major virulence factors including slime, lipase, α-hemolysin, staphyloxanthin and autolysin. Inhibition of staphyloxanthin in turn sensitized the MRSA cells to healthy human blood and hydrogen peroxide (H2O2). Notably, myrtenol treated cells were deficient in extracellular DNA (eDNA) mediated autoaggregation as eDNA releasing autolysis was impaired by myrtenol. Biofilm disruptive activity on preformed biofilms was observed at concentrations higher than minimum biofilm inhibitory concentration (MBIC) of myrtenol. Also, the non-cytotoxic effect of myrtenol on human peripheral blood mononuclear cell (PBMC) was evidenced by trypan blue and Alamar blue assays. Transcriptional analysis unveiled the down-regulation of global regulator sarA and sarA mediated virulence genes upon myrtenol treatment, which is well correlated with results of phenotypic assays. Thus, the results of the present study revealed the sarA mediated antibiofilm and antivirulence potential of myrtenol against MRSA.

Dataset Information

Sub-Inhibitory Concentrations of Mupirocin Strongly Inhibit Alpha-Toxin Production in High-Level Mupirocin-Resistant MRSA by Down-Regulating agr, saeRS, and sarA.

Publications

Sub-Inhibitory Concentrations of Mupirocin Strongly Inhibit Alpha-Toxin Production in High-Level Mupirocin-Resistant MRSA by Down-Regulating <i>agr, saeRS</i>, and <i>sarA</i>.

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