Antibiotics as selectors and accelerators of diversity in the mechanisms of resistance: from the resistome to genetic plasticity in the β-lactamases world

Abstract

Antibiotics and antibiotic resistance determinants, natural molecules closely related to bacterial physiology and consistent with an ancient origin, are not only present in antibiotic-producing bacteria. Throughput sequencing technologies have revealed an unexpected reservoir of antibiotic resistance in the environment. These data suggest that co-evolution between antibiotic and antibiotic resistance genes has occurred since the beginning of time. This evolutionary race has probably been slow because of highly regulated processes and low antibiotic concentrations. Therefore to understand this global problem, a new variable must be introduced, that the antibiotic resistance is a natural event, inherent to life. However, the industrial production of natural and synthetic antibiotics has dramatically accelerated this race, selecting some of the many resistance genes present in nature and contributing to their diversification. One of the best models available to understand the biological impact of selection and diversification are β-lactamases. They constitute the most widespread mechanism of resistance, at least among pathogenic bacteria, with more than 1000 enzymes identified in the literature. In the last years, there has been growing concern about the description, spread, and diversification of β-lactamases with carbapenemase activity and AmpC-type in plasmids. Phylogenies of these enzymes help the understanding of the evolutionary forces driving their selection. Moreover, understanding the adaptive potential of β-lactamases contribute to exploration the evolutionary antagonists trajectories through the design of more efficient synthetic molecules. In this review, we attempt to analyze the antibiotic resistance problem from intrinsic and environmental resistomes to the adaptive potential of resistance genes and the driving forces involved in their diversification, in order to provide a global perspective of the resistance problem.

The multiple roles of antibiotics and antibiotic resistance in nature

“…This brings with it inherent problems of designing experimental procedures and standards that can be used in many different microbiomes from human to soil and is discussed further by Walsh (Walsh, 2013). A number of models are proposed to study and understand the biological impact of selection and diversification of antibiotic resistance mechanisms, in particular using the β-lactamases as models (Galán et al, 2013; Patel and Bonomo, 2013; Popowska and Krawczyk-Balska, 2013). The β-lactamases constitute the most widespread mechanism of resistance, at least among pathogenic bacteria, with more than 1000 enzymes identified in the literature.…”

Un ecosistema malalt: la lluita contra la resistència a antibiòtics des d’una perspectiva global

“…La importàn-cia de la pol·lució antibiòtica del planeta no és tant la selecció de bacteris resistents potencialment patògens per als humans (i per tant causants d'infeccions intractables), sinó sobretot els efectes de caràcter «ecològic» que podrien resultar de l'eliminació de poblacions naturals i la seua substitució per d'altres. Incrementant les forces selectives i estimulant la capacitat de variació dels microorganismes (mutació, recombinació, transposició, modularització, transferència genètica) (Galán et al, 2013) els antibiòtics d'origen industrial estan modifi cant l'ecogenètica dels bacteris i accelerant l'evolució de la microbiosfera. És essencial comprendre que la major part dels antibiòtics són substàncies naturals.…”

Strategies for Circumventing Bacterial Resistance Mechanisms

“…Moreover, sustaining this amelioration will require simultaneous change at each of these three levels (Paphitou 2013;Metz and Shlaes 2014). While the resistome is ancient, the profligate exploitation of the antibiotics has accelerated resistance emergence and galvanized its distribution (Galán et al 2013). While it is uncertain whether an event short of a pandemic will realize this sea change, the scientific and medical objectives for preserving successful antibacterial chemotherapy in the face of a seeming universe of resistance mechanisms are obvious.…”