Antibiotic Resistance Mechanisms in Bacteria: Relationships Between Resistance Determinants of Antibiotic Producers, Environmental Bacteria, and Clinical Pathogens

Abstract

Emergence of antibiotic resistant pathogenic bacteria poses a serious public health challenge worldwide. However, antibiotic resistance genes are not confined to the clinic; instead they are widely prevalent in different bacterial populations in the environment. Therefore, to understand development of antibiotic resistance in pathogens, we need to consider important reservoirs of resistance genes, which may include determinants that confer self-resistance in antibiotic producing soil bacteria and genes encoding intrinsic resistance mechanisms present in all or most non-producer environmental bacteria. While the presence of resistance determinants in soil and environmental bacteria does not pose a threat to human health, their mobilization to new hosts and their expression under different contexts, for example their transfer to plasmids and integrons in pathogenic bacteria, can translate into a problem of huge proportions, as discussed in this review. Selective pressure brought about by human activities further results in enrichment of such determinants in bacterial populations. Thus, there is an urgent need to understand distribution of resistance determinants in bacterial populations, elucidate resistance mechanisms, and determine environmental factors that promote their dissemination. This comprehensive review describes the major known self-resistance mechanisms found in producer soil bacteria of the genus Streptomyces and explores the relationships between resistance determinants found in producer soil bacteria, non-producer environmental bacteria, and clinical isolates. Specific examples highlighting potential pathways by which pathogenic clinical isolates might acquire these resistance determinants from soil and environmental bacteria are also discussed. Overall, this article provides a conceptual framework for understanding the complexity of the problem of emergence of antibiotic resistance in the clinic. Availability of such knowledge will allow researchers to build models for dissemination of resistance genes and for developing interventions to prevent recruitment of additional or novel genes into pathogens.

Keywords: Streptomyces; antibiotic resistance; clinical pathogens; environmental bacteria; horizontal gene transfer; producer bacteria; resistance gene dissemination; self-resistance mechanisms.

FIGURE 1

Schematic representation of different antibiotic resistance mechanisms in bacteria, shown with examples. (A) Antibiotic modification involves the addition of acetyl, phosphate, or adenyl groups to aminoglycosides by N-acetyl transferases (AAC), O-phosphotransferases (APH), and O-adenyltransferases (ANT). Other examples include chloramphenicol acetyl transferases (CAT) and bleomycin N-acetyltransferases (BlmB). (B) Antibiotic degradation is observed with β-lactamases, which hydrolyze the antibiotic. (C) Antibiotic efflux pumps remove the antibiotic from the cell using energy from ATP hydrolysis in ABC pumps like DrrAB, OtrC, TlrC, and MlbYZ, or proton gradients in MFS, MATE, SMR, and RND family pumps. (D) Target modification includes various target alterations, such as 23S rRNA or 16S rRNA methylation, alterations in the peptidoglycan precursors (for example, in the case of glycopeptides), or synthesis of alternate low-affinity targets (PBPs) that reduce or completely block antibiotic (penicillins) from associating with the target. (E) Antibiotic sequestration involves proteins that can associate with the antibiotic and block them from reaching their targets. (F) Target bypass involves generation of additional antibiotic targets or subunits that are not susceptible to binding of the antibiotic. Meth, methylation.

FIGURE 2

Schematic showing reservoirs of antibiotic resistance genes found in nature and various pathways for their movement to the clinic. Transfer of resistance genes to clinical isolates could occur by a variety of routes (shown by arrows), each using horizontal gene transfer mechanisms potentially involving plasmids, integrons, or transposons. While direct transfer of resistance determinants from producers in the soil to clinical strains is possible (Route 1), a more likely route may first involve movement from the producer soil bacteria to non-producer soil bacteria (for example Mycobacterium species) (Pang et al., 1994) (Route 2A), followed by transfer to clinical pathogens through several carriers (Route 2B). Another, possibly more important route, could involve direct transfer from environmental bacteria (found in bodies of water, aquaculture, livestock animals, wildlife, and plants) to clinical isolates (Route 3). Routes 2 and 3 are shown as thick red arrows, implying greater probability of these pathways for dissemination of resistance genes to clinical strains.