Collateral sensitivity and cross-resistance in six species of bacteria exposed to six classes of antibiotics

De novo resistance can develop in bacteria as a result of exposure to sublethal concentrations of antibiotics. Once the strain has become resistant to an initial antibiotic, this can cause cross-resistance or collateral sensitivity to a second antimicrobial. Specific collateral sensitivity is rarely conserved across species because the mechanisms triggered in different microorganisms to resist antibiotics are often different. In this study, we explored which collateral sensitivity or cross-resistance networks are present in six species of bacteria with induced de novo resistance. These six species were induced to become resistant to amoxicillin/cefepime, enrofloxacin, kanamycin, tetracycline, erythromycin, and chloramphenicol (T. Pulingam, T. Parumasivam, A. M. Gazzali, A. M. Sulaiman, J. Y. Chee, et al., Eur J Pharm Sci 170:106103, 2022, https://doi.org/10.1016/j.ejps.2021.106103 ). In this study, the collateral sensitivity and the cross-resistance networks were evaluated by measuring the increase or decrease of MIC of 13 antibiotics that are often used in the clinic. Collateral sensitivity for kanamycin occurred in five species made resistant to chloramphenicol and tetracycline and for β-lactams in five species made resistant to kanamycin. Genetic analysis revealed that fusA consistently mutated in five bacterial species that exhibited de novo resistance to kanamycin, suggesting that mutations in domain IV of fusA are the primary contributors to the consistent CS phenotype observed in these species. Based on considerations of resistance, a treatment protocol starting with chloramphenicol/tetracycline, followed by kanamycin, and ending with amoxicillin may eliminate bacteria that have developed resistance against the initial treatment.

IMPORTANCE

Collateral sensitivity and cross-resistance influence the outcome of antimicrobial infection treatments. To evaluate the potential effects of these phenomena, collateral sensitivity and the cross-resistance networks were documented by measuring the MIC of six species of bacteria with induced resistance against 13 antibiotics. These effects are indeed, in some cases, clinically relevant. One example was further explored: collateral sensitivity for kanamycin in five species made resistant to chloramphenicol and tetracycline and for β-lactams in five species made resistant to kanamycin. In this case, genetic analysis revealed that fusA consistently mutated in the five bacterial species that exhibited de novo resistance to kanamycin. The observed collateral sensitivity can be explained by these mutations.