Abstract
In bacteria, evolution of resistance to one antibiotic is frequently associated with increased resistance (cross‐resistance) or increased susceptibility (collateral sensitivity) to other antibiotics. Cross‐resistance and collateral sensitivity are typically evaluated at the minimum inhibitory concentration (MIC). However, these susceptibility changes are not well characterized with respect to the mutant prevention concentration (MPC), the antibiotic concentration that prevents a single‐step mutation from occurring. We measured the MIC and the MPC for Staphylococcus epidermidis and 14 single‐drug resistant strains against seven antibiotics. We found that the MIC and the MPC were positively correlated but that this correlation weakened if cross‐resistance did not evolve. If any type of resistance did evolve, the range of concentrations between the MIC and the MPC tended to shift right and widen. Similar patterns of cross‐resistance and collateral sensitivity were observed at the MIC and MPC levels, though more symmetry was observed at the MIC level. Whole‐genome sequencing revealed mutations in both known‐target and nontarget genes. Moving forward, examining both the MIC and the MPC may lead to better predictions of evolutionary trajectories in antibiotic‐resistant bacteria.
Highlights
In recent decades, there has been a rapid increase in the prevalence of multi-antibioticresistant pathogens (Dijkshoorn, Nemec, Nemec, & Seifert, 2007; Leski et al, 2016; Nordmann, Naas, Naas, Fortineau, & Poirel, 2007; Tandogdu et al, 2016; Zalacain et al, 2016)
We found an increase in the median minimum inhibitory concentration (MIC) and the median mutant prevention concentration (MPC) for all 14 spontaneous mutantresistant strains of S. epidermidis (Table 1) except TET R2
The MPC, unlike the MIC, is not a single value but could vary significantly due to Luria-Delbruck fluctuations (Gianvecchio et al, 2019; Jones, Thomas, Thomas, & Rogers, 1994; Luria & Delbrück, 1943). Despite this variation in MPC values, we generally found that patterns of the types of cross-resistance are common within antibiotic classes at both the MIC and MPC levels, which may be attributed to the types of mutations they share
Summary
There has been a rapid increase in the prevalence of multi-antibioticresistant pathogens (Dijkshoorn, Nemec, Nemec, & Seifert, 2007; Leski et al, 2016; Nordmann, Naas, Naas, Fortineau, & Poirel, 2007; Tandogdu et al, 2016; Zalacain et al, 2016). A small number of recent studies have started to examine collateral effects at the mutant prevention concentration (MPC; Imamovic & Sommer, 2013; Podnecky et al, 2018), which is the concentration at which no single-step resistant mutant can occur (Baquero & Negri, 1997; Bush et al, 2011; Dong, Zhao, Zhao, Domagala, & Drlica, 1999; Drlica, 2003; Drlica & Zhao, 2007). Another study showed that fluoroquinolone-resistant E. coli containing mutations in a topoisomerase gene (gyrA) have changed susceptibility of the bacteria to other antibiotics These changes include increases in resistance to ampicillin, cefoxitin, ciprofloxacin, nalidixic acid, kanamycin, and tobramycin and increases in sensitivity to nitrofurantoin and doxycycline (Lázár et al, 2014). We sequenced their genomes and identified mutations affecting resistance
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