Abstract
The increase of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) poses a worldwide and serious health threat. Although new antibiotics, such as daptomycin and linezolid, have been developed for the treatment of infections of Gram-positive pathogens, the emergence of daptomycin-resistant and linezolid-resistant strains during therapy has now increased clinical treatment failures. In the past few years, studies using quantitative proteomic methods have provided a considerable progress in understanding antibiotic resistance mechanisms. In this review, to understand the resistance mechanisms to four clinically important antibiotics (methicillin, vancomycin, linezolid, and daptomycin) used in the treatment of Gram-positive pathogens, we summarize recent advances in studies on resistance mechanisms using quantitative proteomic methods, and also examine proteins playing an important role in the bacterial mechanisms of resistance to the four antibiotics. Proteomic researches can identify proteins whose expression levels are changed in the resistance mechanism to only one antibiotic, such as LiaH in daptomycin resistance and PrsA in vancomycin resistance, and many proteins simultaneously involved in resistance mechanisms to various antibiotics. Most of resistance-related proteins, which are simultaneously associated with resistance mechanisms to several antibiotics, play important roles in regulating bacterial envelope biogenesis, or compensating for the fitness cost of antibiotic resistance. Therefore, proteomic data confirm that antibiotic resistance requires the fitness cost and the bacterial envelope is an important factor in antibiotic resistance.
Highlights
Antibiotic resistance has posed a serious threat to the worldwide public health in the past two decades
Specific genetic determinants of resistance mechanisms to methicillin, vancomycin, and linezolid were identified through non-proteomic approaches (Table 1), recent comparative proteomic methods provide new opportunities to understand the antibiotic resistance mechanism
Quantitative proteomic methods can be a good tool to find an important protein involved in daptomycin resistance
Summary
Antibiotic resistance has posed a serious threat to the worldwide public health in the past two decades. Methicillin and other β-lactam antibiotics are structural analogs of D-AlaD-Ala, which is the terminus of a short amino acid chain attached in N-acetylmuramic acids; so, they interact with and irreversibly inhibit the transpeptidase enzyme [ called penicillin-binding protein (PBP)] that crosslinks the linear peptidoglycan polymer chains (Lee et al, 2012). This process leads to loss of osmotic integrity and makes the bacterial cells susceptible to lysis. Vancomycin Vancomycin made by the soil bacterium Amycolatopsis orientalis is a member of the glycopeptide antibiotic class and has an TABLE 1 | Modes of action of four clinically important antibiotics (methicillin, vancomycin, linezolid, and daptomycin) and resistance mechanisms to these antibiotics
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