On the evolutionary ecology of multidrug resistance in bacteria

Abstract

Antibiotic resistance, and in particular, multidrug resistance are public health concerns. Yet, there has been little theoretical work on the evolutionary dynamics of multidrug resistance (MDR). Here, we present a generic model of MDR inspired by two pervasive trends in resistance dynamics. The first trend is the robust coexistence of antibiotic sensitivity and resistance in multiple bacterial species and for numerous antibiotics. The second is that resistance to different antibiotics tends to be concentrated on the same strains, giving rise to high MDR frequencies. We argue that these two observations are linked: mechanisms that maintain coexistence also promote high MDR frequencies. This argument is based on the recognition that, in many of the most plausible models of coexistence, the coexistence-maintaining mechanism is fundamentally similar: either strain or host population structure stratifies the pathogen population into sub-populations and introduces variation in the fitness effect of resistance between these sub-populations. We show that this model structure also gives rise to high MDR frequencies, because resistance against all antibiotics is concentrated in the sub-populations where the fitness advantage gained from resistance is high. We test predictions from this model on two pneumococcal datasets and find predicted trends are qualitatively consistent with those observed in data. This model provides a parsimonious explanation for the pervasiveness of high MDR frequencies and allows us to reconcile this trend with observed long-term stability in the prevalence of resistance.

Mass drug administration with azithromycin for trachoma elimination and the population structure of Streptococcus pneumoniae in the nasopharynx

“…Although the numbers are small, all isolates that carried macrolide resistance genes concurrently carried the tetracycline resistance gene tet(M) in a mobile genetic element. If MDA selects for strains carrying mobile genetic elements, often encoding multiple antibiotic resistance genes, there is potential for increases in multidrug resistance [37]. Macrolide resistance was at undetectable levels in this study before the intervention, in other settings with established macrolide resistance in pneumococci, the potential for rises in macrolide-resistant pneumococci after MDA with azithromycin may be greater.…”

The evolution of antibiotic resistance in a structured host population

“…In future work, the major challenge will be to integrate more details of the host population and bacterial genotypes, in order to reproduce the observed pattern of resistance across settings, while retaining tractability and a good understanding of the model behaviour. This would allow more insights into the dynamics of resistance, estimating more precisely the cost of resistance, assessing the impact of a vaccine on resistance (for example, the pneumococcal conjugate vaccine against S. pneumoniae ), and identifying the evolutionary forces selecting for multidrug resistance [ 47 ].…”

Tackling Multidrug Resistance in Streptococci – From Novel Biotherapeutic Strategies to Nanomedicines

“…Metagenomics directly analyze DNA in a biological sample, allowing for analysis of the resistome within distinct microbial ecosystems ( Von Wintersdorff et al, 2016 ). These studies highlight that determinants of antibiotic resistance, including those clinically relevant, are prevalent in these environments ( Lehtinen et al, 2019 ). Sequence-based studies provide large datasets, but one limitation is that they focus on genes already known to be involved in the resistance, or (less frequently) to predict new functions based on the homology to known sequences.…”

“…The acquisition of mobile genetic elements (MGEs), such as bacteriophages, plasmids, integrative and conjugative elements, is recognized as a key point in the emergence of multidrug-resistant (MDR) strains ( Lehtinen et al, 2019 ). The main mechanisms of DNA uptake in bacteria are conjugation, transduction, and transformation ( Figure 2 ), which must be followed by recombination to allow stable insertion into the chromosome.…”

“…However, the benefits of antibiotics were lost considerably with the emergence and dissemination of bacterial resistance. The emergence of infectious diseases caused by multidrug-resistant bacterial generated an essential need for alternatives approaches to traditional antibiotics ( Chang et al, 2015 ; Lehtinen et al, 2019 ). Along these lines, bacteriophages and phage-derived protein therapy get revitalized.…”