Mutational Evolution of Pseudomonas aeruginosa Resistance to Ribosome-Targeting Antibiotics

Abstract

The present work examines the evolutionary trajectories of replicate Pseudomonas aeruginosa cultures in presence of the ribosome-targeting antibiotics tobramycin and tigecycline. It is known that large number of mutations across different genes – and therefore a large number of potential pathways – may be involved in resistance to any single antibiotic. Thus, evolution toward resistance might, to a large degree, rely on stochasticity, which might preclude the use of predictive strategies for fighting antibiotic resistance. However, the present results show that P. aeruginosa populations evolving in parallel in the presence of antibiotics (either tobramycin or tigecycline) follow a set of trajectories that present common elements. In addition, the pattern of resistance mutations involved include common elements for these two ribosome-targeting antimicrobials. This indicates that mutational evolution toward resistance (and perhaps other properties) is to a certain degree deterministic and, consequently, predictable. These findings are of interest, not just for P. aeruginosa, but in understanding the general rules involved in the evolution of antibiotic resistance also. In addition, the results indicate that bacteria can evolve toward higher levels of resistance to antibiotics against which they are considered to be intrinsically resistant, as tigecycline in the case of P. aeruginosa and that this may confer cross-resistance to other antibiotics of therapeutic value. Our results are particularly relevant in the case of patients under empiric treatment with tigecycline, which frequently suffer P. aeruginosa superinfections.

Molecular Characteristics and Antimicrobial Susceptibility Profile of Pseudomonas aeruginosa isolated from patients attending Healthcare Facilities in Mthatha, South Africa

“…The reported increasing penicillinase-producing β-lactamases strains among these organisms validates the noticeably observable high rate resistance of our isolates to piperacillin [42]. Antibiotic resistance is a public health menace with an alarming proportion that is getting collective attention more so that several studies have found a correlation between level of antibiotic prescription with the prevalence of antibiotic resistance [43][44]. Patients with resistant P. aeruginosa infections have a poor prognosis hence it is imperative that P. aeruginosa strains presenting severe drug resistance is monitored [23].…”

Parallel evolution of tobramycin resistance across species and environments

“…While A. baumannii has one copy of fusA1 , P. aeruginosa and other Pseudomonas species also harbor an additional copy encoded by the gene fusA2 (Palmer et al, 2013). EF-G is not known to be a direct binding target of TOB, and has received little attention as a mechanism of resistance to aminoglycosides in these species (Bolard et al, 2017; Sanz-García et al, 2018). However, this protein is the direct binding target of other antibiotics including fusidic acid and argyrin B (Johanson and Hughes, 1994; Jones et al, 2017).…”

“…The exact mechanism by which mutations in EF-G confer aminoglycoside resistance is currently unknown but this study demonstrates it is an important resistance determinant. The ptsP gene encodes phosphoenolpyruvate phosphotransferase protein, which is part of the nitrogen phosphotransferase system and has previously been identified as a target of aminoglycoside resistance for P. aeruginosa , but not A. baumannii (Sanz-García et al, 2018; Schurek et al, 2008). The mechanism by which mutations in ptsP may confer resistance to TOB is also unknown, although the nitrogen phosphotransferase system has been shown to regulate expression of genes responsible for coordinating the antibiotic stress response, suggesting an indirect link between the nitrogen phosphotransferase system and antibiotic resistance (Gebhardt and Shuman, 2017).…”

“…The rapidly intensifying problem of antimicrobial resistance demands understanding of how antibiotic resistance evolves and which types of mutations or mobile elements are common causes (Brockhurst et al, 2019). Genetic screens of mutant collections have revealed potential resistance mechanisms (Schurek et al, 2008), and more recently, evolve-and-resequence experiments have been used to identify the most fit resistance mutations in a given condition (Santos-Lopez et al, 2019; Sanz-García et al, 2018; Wong et al, 2012). However, the broader clinical utility of these screens for predicting the evolution of antibiotic resistance depends upon the relevance of the findings in other genetic backgrounds or environments.…”

Mechanistic origin of drug interactions between translation-inhibiting antibiotics

“…3D). Furthermore, mutations in recycling factor were selected in Pseudomonas aeruginosa evolved for resistance to the TET derivative tigecycline [Sanz-Garcia et al , 2018]. The observed alleviation of TET action by a recycling bottleneck (Fig.…”