Evolutionary consequences of antibiotic use for the resistome, mobilome and microbial pangenome

Abstract

The widespread use and abuse of antibiotic therapy has evolutionary and ecological consequences, some of which are only just beginning to be examined. One well known consequence is the fixation of mutations and lateral gene transfer (LGT) events that confer antibiotic resistance. Sequential selection events, driven by different classes of antibiotics, have resulted in the assembly of diverse resistance determinants and mobile DNAs into novel genetic elements of ever-growing complexity and flexibility. These novel plasmids, integrons, and genomic islands have now become fixed at high frequency in diverse cell lineages by human antibiotic use. Consequently they can be regarded as xenogenetic pollutants, analogous to xenobiotic compounds, but with the critical distinction that they replicate rather than degrade when released to pollute natural environments. Antibiotics themselves must also be regarded as pollutants, since human production overwhelms natural synthesis, and a major proportion of ingested antibiotic is excreted unchanged into waste streams. Such antibiotic pollutants have non-target effects, raising the general rates of mutation, recombination, and LGT in all the microbiome, and simultaneously providing the selective force to fix such changes. This has the consequence of recruiting more genes into the resistome and mobilome, and of increasing the overlap between these two components of microbial genomes. Thus the human use and environmental release of antibiotics is having second order effects on the microbial world, because these small molecules act as drivers of bacterial evolution. Continued pollution with both xenogenetic elements and the selective agents that fix such elements in populations has potentially adverse consequences for human welfare.

Integrons: Past, Present, and Future

“…They have also made their way into plant pathogens (151) and Gram-positive organisms (152). Their general abundance in human-dominated ecosystems and their release via human waste streams means that clinical class 1 integrons are increasingly being reported as "pollutants" of natural environments (144,153).…”

Impact of Dental Plaque Biofilms in Periodontal Disease: Management and Future Therapy

“…The widespread use of antibiotics has evolutionary and ecological consequences, leading to the recruitment of more genes into the resistome and mobilome, with adverse consequences for human welfare [108], so new approaches are urgently needed to help regain control over infectious diseases, including periodontal disease.…”

New Structural Templates for Clinically Validated and Novel Targets in Antimicrobial Drug Research and Development

“…This is most probably also true for purely synthetic antibiotics, as nature provides natural product antibiotics directed to nearly every known druggable target in bacteria (Lin et al 1997;Keller et al 2007;Johnston et al 2016). Furthermore, we have to consider that every time an antibiotic is administered there is a significant influence on the resistome (Gillings 2013), which is defined as the collection of all genes in pathogenic and non-pathogenic bacteria that could contribute to a phenotype of antibiotic resistance (Frankel et al 2006;Wright 2007;Wright 2010;Forsberg et al 2012;Gillings 2013;Nesme and Simonet 2015). This influence can lead to the evolution of resistance also in non-pathogenic bacteria in the patient or after clearance of the drug into the general environment, i.e.…”

“…The anthropological reasons for this situation are manifold; they include the inadequate clinical use of existing antibiotics (Gilbert 2015;Sanchez and Demain 2015;Shiva 2015), extended misuse of antibiotics in intensive animal husbandry for food production (Bengtsson and Greko 2014;Littmann et al 2015), and the economically-driven exodus of big pharma companies from the antibiotics research field that contributed to the innovation gap mentioned above (Lowther 1979;Powers 2003;Projan 2003;Spellberg et al ; Tau es ; To es ; O Co ell et al . Beyond these anthropological acceleration forces (Breu et al 2001;Gillings 2013), we have to accept that bacterial resistance to antibiotics is not a side effect of modern drug therapy, but an inherent part of bacterial evolution to fight for their evolutionary niche with other bacteria and further organisms (Wright 2012;Wright and Poinar 2012;Rodríguez-Rojas et al 2013). It has been estimated that bacteria producing antibacterial metabolites originated at least hundreds of millions of years ago (Baltz 2008;Wright and Poinar 2012).…”