The fitness cost of streptomycin resistance depends on rpsL mutation, carbon source and RpoS (sigmaS).
Mutations that cause antibiotic resistance often produce associated fitness costs. These costs have a detrimental effect on the fate of resistant organisms in natural populations and could be exploited in designing drugs, therapeutic regimes, and intervention strategies. The streptomycin resistance (StrR) mutations K42N and P90S in ribosomal protein S12 impair growth on rich medium. Surprisingly, in media with poorer carbon sources, the same StrR mutants grow faster than wild type. This improvement reflects a failure of these StrR mutants to induce the stress-inducible sigma factor RpoS (sigmaS), a key regulator of many stationary-phase and stress-inducible genes. On poorer carbon sources, wild-type cells induce sigmaS, which retards growth. By not inducing sigmaS, StrR mutants escape this self-imposed inhibition. Consistent with this interpretation, the StrR mutant loses its advantage over wild type when both strains lack an RpoS (sigmaS) gene. Failure to induce sigmaS produced the following side effects: (1) impaired induction of several stress-inducible genes, (2) reduced tolerance to thermal stress, and (3) reduced translational fidelity. These results suggest that RpoS may contribute to long-term cell survival, while actually limiting short-term growth rate under restrictive growth conditions. Accordingly, the StrR mutant avoids short-term growth limitation but is sensitized to other stresses. These results highlight the importance of measuring fitness costs under multiple experimental conditions not only to acquire a more relevant estimate of fitness, but also to reveal novel physiological weaknesses exploitable for drug development.
Paulander
Wilhelm
W
Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
Maisnier-Patin
Sophie
S
Andersson
Dan I
DI
D019943:Amino Acid Substitution; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D005990:Glycerol / Q000378:metabolism / Q000494:pharmacology; D050296:Microbial Viability / Q000187:drug effects; D009154:Mutation; D011773:Pyruvates / Q000378:metabolism / Q000494:pharmacology; D012269:Ribosomal Proteins / Q000235:genetics* / Q000378:metabolism; D012486:Salmonella typhimurium / Q000166:cytology / Q000235:genetics / Q000378:metabolism; D012808:Sigma Factor / Q000235:genetics* / Q000378:metabolism; D013307:Streptomycin / Q000494:pharmacology; D013386:Succinates / Q000378:metabolism / Q000494:pharmacology; D013696:Temperature
D001426:Bacterial Proteins; D011773:Pyruvates; D012269:Ribosomal Proteins; D012808:Sigma Factor; D013386:Succinates; C034212:ribosomal protein S12; C069567:sigma factor KatF protein, Bacteria; D005947:Glucose; D005990:Glycerol; D013307:Streptomycin