Allogenous Selection of Mutational Collateral Resistance: Old Drugs Select for New Resistance Within Antibiotic Families

Abstract

Allogeneous selection occurs when an antibiotic selects for resistance to more advanced members of the same family. The mechanisms of allogenous selection are (a) collateral expansion, when the antibiotic expands the gene and gene-containing bacterial populations favoring the emergence of other mutations, inactivating the more advanced antibiotics; (b) collateral selection, when the old antibiotic selects its own resistance but also resistance to more modern drugs; (c) collateral hyper-resistance, when resistance to the old antibiotic selects in higher degree for populations resistant to other antibiotics of the family than to itself; and (d) collateral evolution, when the simultaneous or sequential use of antibiotics of the same family selects for new mutational combinations with novel phenotypes in this family, generally with higher activity (higher inactivation of the antibiotic substrates) or broader spectrum (more antibiotics of the family are inactivated). Note that in some cases, collateral selection derives from collateral evolution. In this article, examples of allogenous selection are provided for the major families of antibiotics. Improvements in minimal inhibitory concentrations with the newest drugs do not necessarily exclude “old” antibiotics of the same family of retaining some selective power for resistance to the newest agents. If this were true, the use of older members of the same drug family would facilitate the emergence of mutational resistance to the younger drugs of the family, which is frequently based on previously established resistance traits. The extensive use of old drugs (particularly in low-income countries and in farming) might be significant for the emergence and selection of resistance to the novel members of the family, becoming a growing source of variation and selection of resistance to the whole family. In terms of future research, it could be advisable to focus antimicrobial drug discovery more on the identification of new targets and new (unique) classes of antimicrobial agents, than on the perpetual chemical exploitation of classic existing ones.

Phylogenomics of globally spread Clonal Groups 14 and 15 of Klebsiella pneumoniae

“…In fact, fluoroquinolone resistance seems to be an advantage for the fitness of high-risk clones of different species (40, 41). Fluoroquinolone resistant clones predominate in the elderly and people with previous exposure to healthcare centers that facilitates the acquisition of other antibiotic resistances (43, 44).…”

Low Ciprofloxacin Concentrations Select Multidrug-Resistant Mutants Overproducing Efflux Pumps in Clinical Isolates of Pseudomonas aeruginosa

“…Further, the cross-resistance phenotype to the distinct drugs was rather conserved and robust among the biological replicates (Table S2). The most frequent cross-resistance was to levofloxacin, an example of allogenous selection of cross-resistance ( 50 ). This is not unexpected, since this antimicrobial is also a quinolone; hence, its mechanisms of action and resistance can be similar to those of ciprofloxacin.…”

Deciphering the genetic network and programmed regulation of antimicrobial resistance in bacterial pathogens

“…Collateral-resistance/allogenous selection occurs when an antibiotic induces mutation(s) that express resistance to the second antibiotic. This form of selection has been described in aminoglycosides, β-lactams, macrolides, tetracyclines, and quinolones/fluoroquinolones ( Baquero et al., 2021 ). Many other interactions between antibiotics and biocides/heavy metals, may have co-selective or counter-selective consequences on AMR ( Gilbert and McBain, 2003 ; Ciric et al., 2011 ; Rensch et al., 2013 ).…”