Differences in Antibiotic-Induced Oxidative Stress Responses between Laboratory and Clinical Isolates of Streptococcus pneumoniae

Abstract

ABSTRACTOxidants were shown to contribute to the lethality of bactericidal antibiotics in different bacterial species, including the laboratory strainStreptococcus pneumoniaeR6. Resistance to penicillin amongS. pneumoniaeR6 mutants was further shown to protect against the induction of oxidants upon exposure to unrelated bactericidal compounds. In the work described here, we expanded on these results by studying the accumulation of reactive oxygen species in the context of antibiotic sensitivity and resistance by includingS. pneumoniaeclinical isolates. InS. pneumoniaeR6, penicillin, ciprofloxacin, and kanamycin but not the bacteriostatic linezolid, erythromycin, or tetracycline induced the accumulation of reactive oxygen species. For the three bactericidal compounds, resistance to a single molecule prevented the accumulation of oxidants upon exposure to unrelated bactericidal antibiotics, and this was accompanied by a reduced lethality. This phenomenon does not involve target site mutations but most likely implicates additional mutations occurring early during the selection of resistance to increase survival while more efficient resistance mechanisms are being selected or acquired. Bactericidal antibiotics also induced oxidants in sensitiveS. pneumoniaeclinical isolates. The importance of oxidants in the lethality of bactericidal antibiotics was less clear than forS. pneumoniaeR6, however, since ciprofloxacin induced oxidants even in ciprofloxacin-resistantS. pneumoniaeclinical isolates. Our results provide a clear example of the complex nature of the mode of action of antibiotics. The adaptive approach to oxidative stress ofS. pneumoniaeis peculiar, and a better understanding of the mechanism implicated in response to oxidative injury should also help clarify the role of oxidants induced by antibiotics.