Abstract
Staphylococcus aureus is one of the most successful opportunistic pathogen able to cause serious infections due to its ability to produce virulence factors and acquire antimicrobial resistance. Recent reports indicate that the phenotypic changes in the cell wall and cell membrane are essential mechanisms related to the resistance to several antibacterial drugs (such as daptomycin and vancomycin). These alterations involve changes in cell wall composition and chemical modifications of some components (point mutation leading to modification in phosphatidylglycerol molecule, in the production of the aberrations in peptidoglycan structure and decrease in autolytic activity of the components of the cell envelope), leading to changes in electric charge of the cell surface, cell membrane fluidity and cell morphology. In fact, S. aureus develops several multifactorial and strain-specific adaptive mechanisms to survival in host. The study of such mechanisms is very important. The aim of this chapter is to review the phenotypic mechanisms related to drug resistance in S. aureus.
Keywords
- Staphylococcus aureus
- daptomycin
- vancomycin
- heteroresistance
- stress stimulon response
1. Introduction
The lipopeptide and glycopeptide antibiotics are very effective against infections caused by Gram-positive cocci, showing good efficacy against
Daptomycin (DAP) is a cyclic lipopeptide antibiotic obtained from
The glycopeptide antibiotics were introduced in therapy against infections caused by
Heteroresistance is defined as resistance to antibiotics expressed by a subset of a microbial population that initially is considered susceptible to these antibiotics. These resistant subpopulations are able to adapt to increasing drug concentrations in a stepwise manner [12]. This phenomenon has been described in a wide range of bacteria and fungi, but attention has been directed toward
VISA and hVISA have an increased D-Ala-D-Ala moieties in their thickness cell wall that form false targets that sequester vancomycin, with reduced autolytic activity and slow growth in vitro ([14]. This phenomenon is believed to “trap” vancomycin and this, together with the thickened cell wall, may act as a barrier to the diffusion of large molecules, like daptomycin (as cited below) [16, 17]. In this way, the emergence of these bacterial phenotypes cited above has put into question the effectiveness of these antibiotics against
2. Mechanisms for daptomycin resistance associated to modifications in cell membrane of the Staphylococcus aureus
A few years ago, antibiotic therapy using DAP to treat MRSA infections appeared to be a good choice; however, there are reports in the literature about bacterial strains with resistance to daptomycin (DAP-R) and with intermediary resistance (DAP-I) [19, 22].
The lysyl-phosphatidylglycerol (Lys-PG) is an important membrane lipid in bacteria, more common in Gram-positive cells [28]. The Lys-PG is incorporated into the microbial cell membrane by the activity
The MprF protein catalyzes the modification of the negatively charged in phosphatidylglycerol (PG) with l-lysine and translocation of Lys-PG from the inside to the outside of the cell membrane leaflet [30]. MprF proteins in
The neutralization of the cell membrane surface leads to MprF triggered by bacterial resistance to cationic antimicrobial peptides (CAMPs) [31]. MprF was first described as a virulence factor of
Several hypotheses have been raised about the interference mechanisms of a mutant gene for the MprF protein in the dynamics of PG synthesis in
3. Mechanisms for vancomycin resistance associated to modifications in cell envelope of the Staphylococcus aureus
The resistance mechanisms for both VISA and hVISA appear to have common features. However, it is always observed in patterns that distinguish them from vancomycin-susceptible
Studies conducted on gene transcription analysis showed that after exposure of DAP, the cells exhibit a regulation of the cell wall “stimulon,” similar to that observed in response to vancomycin [1, 38]. Comparison of DAP-I and DAP-
Signal transduction mediated by two-component systems (TCSs)
The assessment of the effects of mutations directed at specific targets, which are responsible for the metabolism of the cell wall in
The ATP-dependent Clp protease (ClpP) consists of two heptameric rings and belongs to the family of serine peptidases [43]. ClpP plays an essential role in the degradation of pathogen cell wall but also in the regulation of their virulence [44]. The ClpP components in
In various pathogenic microorganisms, such as
Recently, a genetic evaluation of vancomycin-intermediate
4. Mechanisms resistant to β-lactam antibiotics associated to penicillin-binding protein in Staphylococcus aureus
With regard to β-lactam antibiotics, one mechanism-conditioned resistance to these antibiotics, mainly to methicillin and others related drugs, is the expression of penicillin-binding protein modified (PBP2s). The PBP2 is a bifunctional protein produced by
The β-lactam antibiotics inhibit PBPs by competing with the precursor [undecaprenyl-pyrophosphoryl-MurNAc-(pentapeptide)] for binding to the active site of the enzyme. PBP2s enzymes are associated with decreased bacterial susceptibility to oral cephalosporins and recently, they have been implicated in the emergence of the “MRSA superbugs” [54]. One of the most worrisome evidence on MRSA is related to high mortality rates among infected patients. It is estimated that for MRSA patients, the mortality rate is two to three times higher than for patients infected with
In methicillin-resistant
5. The cell-wall-stress stimulon response in Staphylococcus aureus
Some antibiotics related to cell wall biogenesis and its stability can influence gene expression and produce a cell-wall-stress stimulon (CWSS) in the
Recently, by using a reporter gene system based on a highly sensitive luciferase fused with
6. Conclusion
Multiple mechanisms contribute to the increased antimicrobial resistance in S. aureus, culminating in a more robust cellular adaptation against antibiotics that act on the synthesis of components of the cell envelope. These multiple mechanisms of adaptation in
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