Unusual and Unconsidered Mechanisms of Bacterial Resilience and Resistance to Quinolones

Abstract

Quinolone resistance has been largely related to the presence of specific point mutations in chromosomal targets, with an accessory role of impaired uptake and enhanced pump-out. Meanwhile the relevance of transferable mechanisms of resistance able to protect the target of pump-out or inactivate quinolones has been increasingly reported since 1998. Nevertheless, bacteria have other strategies and mechanisms allowing them to survive and even proliferate in the presence of quinolones, which might be qualified as resistance or resilience mechanisms. These include decreasing levels of quinolone target production, transient amoeba protection, benthonic lifestyle, nutrient-independent slow growth, activation of stringent response, inactivation or degradation of quinolones as well as apparently unrelated or forgotten chromosomal mutations. These mechanisms have been largely overlooked, either because of the use of classical approaches to antibiotic resistance determination or due to the low increase in final minimum inhibitory concentration levels. This article is devoted to a review of a series of these mechanisms.

Keywords: RNA polymerase mutation; amoeba; biofilm; quinolone targets; quinolones inactivation; stringent response; toxin/antitoxin systems.

Figure 1

Subclasses of quinolones. At present, 4 subclasses of quinolones (A) quinolines; (B) cinnolines; (C) Pyridopyrimidine; (D) Naphthyridine have been described; atom numeration is described following the quinolines (A) structure, with position 1 risen in the nitrogen atom. The figure also illustrates the structure of 2-Pyridons (E), because they are structurally related, but at present, none have been introduced in human or veterinary practice. Reproduced from reference [1], with permission from the American Society of Microbiology.

Figure 2

Proposed model of independent action of stringent and toxin/antitoxin systems. TA: Toxin/antitoxin system; QS: Quorum sensing; SS: Secretion systems; ROS. Reactive Oxygen Species; T3SS: Type 3 secretion systems. (A) Molecular mechanisms underlying bacterial persistence. (B) Different models explaining the involvement of (p)ppGpp in persistence and representative publications (see reference [135]). (B) red: T/A systems are activated by (p)ppGpp. grey: T/A systems induce quiescence independently; light green: (p)ppGpp protects against oxidative stress, favoring the development of persister cells; dark green: (p)ppGpp induces dimerization of ribosomes, which subsequently lead to persistence. References presents in the figure may be found at [138]. Reproduced from reference [138], with the permission of Elsevier.

Figure 3

Models of development of persister cells. Note that while all pathways are represented as independent routes, different interactions among them may be present. Reproduced from reference [142], published under a Creative Commons license.

Figure 4

Proposed network of metabolites generated from ciprofloxacin by the brown rot fungus Gloeophyllum striatum. (A) Oxidative decarboxylation. (B) Defluorination. (C) Hydroxylation at C-8. (D) Oxidation of the amino moiety. Trace metabolites, detected only by HPLC–MS are represented at a reduced size. Reproduced from reference [158], with the permission of Elsevier.

Figure 5

Effect of glnA on the susceptibility levels to norfloxacin. Norfloxacin disk assay of non-induced (gray bars) and IPTG-induced (white bars) cultures of E. coli BL21(DE3) pLysS containing plasmids with or without the glnA insert. In the cells with the glnA insert, the reduced diameter of the clear zones of inhibition due to induction of glutamine synthetase was statistically significant (p < 0.05). Reproduced from reference [168] with the permission of Elsevier.