Abstract
The understanding of the mechanisms of antibiotic resistance development are fundamental to alert and preview beforehand, the large scale dissemination of resistance to antibiotics, enabling the design of strategies to prevent its spread. The mecA-mediated methicillin resistance conferring resistance to broad-spectrum β-lactams is globally spread in staphylococci including hospitals, farms and community environments, turning ineffective the most widely used and efficient class of antibiotics to treat staphylococcal infections. The use of whole genome sequencing (WGS) technologies at a bacterial population level has provided a considerable progress in the identification of key steps that led to mecA-mediated β-lactam resistance development and dissemination. Data obtained from multiple studies indicated that mecA developed from a harmless core gene (mecA1) encoding the penicillin-binding protein D (PbpD) from staphylococcal species of animal origin (S. sciuri group) due to extensive β-lactams use in human created environments. Emergence of the resistance determinant involved distortion of PbpD active site, increase in mecA1 expression, addition of regulators (mecR1, mecI) and integration into a mobile genetic element (SCCmec). SCCmec was then transferred into species of coagulase-negative staphylococci (CoNS) that are able to colonize both animals and humans and subsequently transferred to S. aureus of human origin. Adaptation of S. aureus to the exogenously acquired SCCmec involved, deletion and mutation of genes implicated in general metabolism (auxiliary genes) and general stress response and the adjustment of metabolic networks, what was accompanied by an increase in β-lactams minimal inhibitory concentration and the transition from a heterogeneous to homogeneous resistance profile. Nowadays, methicillin-resistant S. aureus (MRSA) carrying SCCmec constitutes one of the most important worldwide pandemics. The stages of development of mecA-mediated β-lactam resistance described here may serve as a model for previewing and preventing the emergence of resistance to other classes of antibiotics.
Highlights
Antimicrobial resistance threatens the effective prevention and treatment strategies of an increasing range of bacterial infections
The major driving force for the emergence of β-lactams resistance in staphylococci was the continuous exposure to β-lactams in multiple environments: in soils where they had to co-exist with penicillin-producing fungi; in production animal farms wherein large amounts of β-lactam antibiotics were used as food additives (National Research Council, 1980; Castanon, 2007), and during treatment of bacterial infections (Westh et al, 2004)
Besides mecA, other mec genes have been identified that are associated with β-lactam resistance, namely mecB and mecD in Macrococcus caseolyticus (Baba et al, 2009; Schwendener et al, 2017; Schwendener and Perreten, 2018) and mecC in S. aureus (Garcia-Alvarez et al, 2011; Shore et al, FIGURE 2 | Schematic representation of the structure of mec native region in S. sciuri group species. (A) Structure of mec native region in S. sciuri, S. vitulinus and S. fleurettii in comparison to mec complex A in S. aureus
Summary
Laboratory of Bacterial Evolution and Molecular Epidemiology, Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal. The mecA-mediated methicillin resistance conferring resistance to broad-spectrum β-lactams is globally spread in staphylococci including hospitals, farms and community environments, turning ineffective the most widely used and efficient class of antibiotics to treat staphylococcal infections. The use of whole genome sequencing (WGS) technologies at a bacterial population level has provided a considerable progress in the identification of key steps that led to mecA-mediated β-lactam resistance development and dissemination. Data obtained from multiple studies indicated that mecA developed from a harmless core gene (mecA1) encoding the penicillin-binding protein D (PbpD) from staphylococcal species of animal origin (S. sciuri group) due to extensive β-lactams use in human created environments. The stages of development of mecA-mediated β-lactam resistance described here may serve as a model for previewing and preventing the emergence of resistance to other classes of antibiotics
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