Antimicrobial resistance in enteric bacteria: current state and next-generation solutions

Abstract

Antimicrobial resistance is one of the largest threats to global health and imposes substantial burdens in terms of morbidity, mortality, and economic costs. The gut is a key conduit for the genesis and spread of antimicrobial resistance in enteric bacterial pathogens. Distinct bacterial species that cause enteric disease can exist as invasive enteropathogens that immediately evoke gastrointestinal distress, or pathobionts that can arise from established bacterial commensals to inflict dysbiosis and disease. Furthermore, various environmental reservoirs and stressors facilitate the evolution and transmission of resistance. In this review, we present a comprehensive discussion on circulating resistance profiles and gene mobilization strategies of the most problematic species of enteric bacterial pathogens. Importantly, we present emerging approaches toward surveillance of pathogens and their resistance elements as well as promising treatment strategies that can circumvent common resistance mechanisms.

Keywords: Antimicrobial resistance; enteric pathogen; high-throughput sequencing; metagenomics; mobile genetic element; pathobiont; whole-genome sequencing.

Figure 1.

Major bacterial enteropathogens, antibiotic resistance reservoirs, and pathogenesis in the human gut. (a) The major enteric bacterial species and common reservoirs for proliferation and resistance exchange. (b) A close-up view of the human gut, representing various pathobiont species and pathogenic tendencies. C. diff: Clostridioides difficile, VRE: Vancomycin-resistant enterococcus, BFG: Bacteroides fragilis group. *Indicates E. coli can assume multiple pathogenic manifestations within the gut, as described by Kaper and coauthors. Image made with BioRender.

Figure 2.

Manifestations of drug resistance. Bacteria become less susceptible to antibiotics through multiple mechanisms, from genetic acquisition of resistance to phenotypic responses to antibiotics. These mechanisms fall into three categories: classic mutation (a), horizontal gene transfer (b), and adaptive response (c). (a) Mutation via genome replication or intragenomic rearrangement can result in the acquisition of resistance. This process requires a series of bacterial generations to cause selection in the population for the inheritance of the resistance mutation. (b) Horizontal transfer of genetic material through multiple mechanisms in enteric pathogens, mainly bacterial conjugation, results in the more rapid acquisition of resistance elements. Mobile genetic elements such as integrons (i), plasmids (ii), or transposons (iii) can be transferred by conjugation. (c) An enteric pathogen’s susceptibility to antibiotics can be determined or altered based on the microbial community. In this example, a change in nutrient pools within a polymicrobial community can prompt a change in the inherent susceptibility of certain organisms to a given antibiotic. Often these susceptibility changes are mediated by changes in bacterial metabolism.