Anti-staphylococcus Antibiotics Interfere With the Transcription of Leucocidin ED Gene in Staphylococcus aureus Strain Newman

Abstract

Antibiotics have been described to modulate bacterial virulence gene expression. This study aimed to assess the changes caused by anti-Staphylococcus agents in the transcription of leucocidin ED (lukED) gene of Staphylococcus aureus strain Newman in vitro and in vivo and to determine whether the altered expression is agr dependent. The bacteria were exposed to subinhibitory concentrations [1/2, 1/4, or 1/8 minimal inhibitory concentration (MIC)] of 11 antibiotics, and the expression of lukE and agr-effector RNAIII was determined using qRT-PCR. In vivo experiments were performed to evaluate the impact exerted by six representative antibiotics on the transcription of both genes. Molecular analysis showed that in vitro lukE transcription was dramatically promoted in the Newman strain exposed to sub-MICs of vancomycin, trimethoprim-sulfamethoxazole, clindamycin, gentamicin, daptomycin, and ciprofloxacin and considerably reduced when stimulated by cefazolin, erythromycin, rifampicin, tigecycline, and linezolid. In the murine abscess model, tigecycline significantly decreased the transcription of lukE and the bacterial numbers, whereas vancomycin increased them; although cefazolin increased the lukE expression (contrary to the in vitro effect), it had a remarkable role in reducing bacterial load. The correspondence analysis shows that RNAIII expression varied under seven of 11 antibiotics in vitro, and six drugs in vivo were consistent with lukE transcripts. In conclusion, our data show that anti-Staphylococcus antibiotics exert modulatory effects on lukE expression in vitro and/or in vivo, and the changed expression caused by some drugs may be involved with agr activity, thus providing a guide to choose appropriate agents to avoid promoting bacterial virulence in lukED-positive S. aureus infections.

Staphylococcal Biofilms: Challenges and Novel Therapeutic Perspectives

“…As mentioned above, cell-cell communication by quorum-sensing (QS) is important for staphylococcal biofilm formation, and such a system is an attractive target for anti-biofilm agents. Molecules that inhibit activation of the agr system have been identified, including natural products [ 281 ] and derivatives of the AgrA/AIP peptides, which compete for binding to AgrC and thereby block the activation of the regulatory pathway. It should be noted, however, that such quorum-quenching approaches may have unpredictable effects.…”

Virulence alterations in staphylococcus aureus upon treatment with the sub-inhibitory concentrations of antibiotics

“…The antibiotic resistance of a certain bacterium is phenotypically determined by minimum inhibitory concentrations (MICs), which are defined as the lowest antibiotic concentrations that can inhibit the growth of pathogens in a medium after 18–24 h of culture in vitro. During antibiotic therapy or while living in nature, however, pathogens may encounter the sub-inhibitory concentrations (sub-MICs) of antibiotics due to several situations [1] , [2] . First, antibiotic concentrations decrease to sub-MICs over time after administration as a result of the pharmacokinetics of antibiotics [3] .…”

“…Third, antibiotic sub-MICs may be generated after waste emissions from hospitals and other treatment facilities or pharmaceutical manufacturers. Fourth, antibiotic sub-MICs can occur owing to bacterial evolution and drug-resistant organism formation [1] . Lastly, in stock farming, antimicrobial drugs used at sub-MICs are still allowed in some countries to promote animal production or prevent bacterial infections [9] .…”

“…In addition, the factors responsible for bacterial adherence, motility, and biofilm formation are associated with the virulence of S. aureus . Accumulated studies have demonstrated that S. aureus can develop genetic and phenotypic variations and alter its virulence expression to adapt to stress environments with the sub-MICs of antibiotics [1] , [2] .…”

“…By contrast, the production of S. aureus toxins is significantly suppressed under exposure to the sub-MICs of antimicrobial agents, such as lincosamides and oxazolidinones, which target microbial ribosomes [18] . The most studies concerning the effects of antibiotics at sub-MIC concentrations on the virulence of S. aureus have been conducted in vitro , and the in vivo researches are rare and encouraging [1] , [4] , [5] , [18] . In this review, we summarized the in vitro effects of the sub-MICs of antibiotics on the virulence of S. aureus from the aspects of morphology, virulence expression, bacterial adherence and invasion, biofilm formation, and small-colony variant (SCV) production.…”