Double-Serine Fluoroquinolone Resistance Mutations Advance Major International Clones and Lineages of Various Multi-Drug Resistant Bacteria

Abstract

The major international sequence types/lineages of methicillin-resistant Staphylococcus aureus (MRSA), extended-spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae and ESBL-producing E. coli were demonstrated to have been advanced by favorable fitness balance associated with high-level resistance to fluoroquinolones. The paper shows that favorable fitness in the major STs/lineages of these pathogens was principally attained by the capacity of evolving mutations in the fluoroquinolone-binding serine residues of both the DNA gyrase and topoisomerase IV enzymes. The available information on fitness balance incurred by individual and various combinations of mutations in the enzymes is reviewed in multiple species. Moreover, strong circumstantial evidence is presented that major STs/lineages of other multi-drug resistant bacteria, primarily vancomycin-resistant Enterococcus faecium (VRE), emerged by a similar mechanism. The reason(s) why the major ST/lineage strains of various pathogens proved more adept at evolving favorable mutations than most isolates of the same species remains to be elucidated.

Global Evolution of Pathogenic Bacteria With Extensive Use of Fluoroquinolone Agents

“…The replacement of the double-serine residues in the DNA gyrase and topoisomerase IV enzymes involved in the binding of fluoroquinolones is crucial for the preservation of considerable fitness at high MIC values to fluoroquinolones. It was demonstrated in various species that the gyrA Ser84 and grlA Ser80 (or corresponding) residues are not optimal for the function of the enzymes and their replacement by some other amino acids is associated with a modest fitness gain in the isolates, in a clone-dependent fashion [reviewed by Fuzi et al (2017)].…”

“…Varying fitness effects (diverse speed of replication 1 ) associated with high-level resistance to fluoroquinolones was demonstrated to confer an indirect growth advantage onto the international clone/ST strains of HA-MRSA (Horváth et al, 2012;Knight et al, 2012;Holden et al, 2013), ESBL-producing K. pneumoniae (Toth et al, 2014), ESBL-producing E. coli (Johnson et al, 2015a,b) and C. difficile (Wasels et al, 2015;Vernon et al, 2019) compared with minor clone isolates that should have contributed to the selection of the international clones/STs in these species [reviewed by Fuzi (2016) and Fuzi et al (2017)]. A "fluoroquinolone connection" could also account for the puzzling time period -the last three decades -for the emergence and dissemination of the international clones and 1 The term fitness always refers to speed of replication in the manuscript.…”

“…Growth tests, epidemiological observations and genetic data all support a role for fluoroquinolones in the selection and dissemination of the internatinal clones/STs of HA-MRSA, MDR K. pneumoniae, MDR E. coli and C. difficile [reviewed by Fuzi (2016) and Fuzi et al (2017)]. This paper will present additional information, published most recently on the fitness, epidemiology and genetics of these pathogens and will analyze the role of virulence factors in the spread of these agents.…”

Simulating multi-level dynamics of antimicrobial resistance in a membrane computing model

“…We show that the speed and intensity of this process depends on the global resistance landscape and the density and phenotype of the bacterial subpopulations. Our model predicts that previous mutational ciprofloxacin-resistance facilitates fast evolution of multi-resistance by horizontal acquisition of resistance genes (14,15). We also show that the long-term dissemination of chromosomally-encoded genes is by far less effective than the spread of traits encoded in transferable plasmids, even though some limitations are detectable because of plasmid incompatibility.…”

“…The overall success of the plasmid PL1 (blue line) benefits from the fact that this mobile element is selected by two different antibiotics (AbA and AbC, resistance shown in red and green lines respectively). Interestingly, resistance to AbFR (violet) is selected from early stages of the experiment, and after 4,000 steps it converges with the AbCR, a plasmid-mediated trait, meaning that this plasmid is maintained almost exclusively in strains harboring AbFR gene, similar to empirical findings (14,15). If the conjugation rate of PL1 was increased, the main effect…”