Very low cefotaxime concentrations select for hypermutable Streptococcus pneumoniae populations

Area of Science:

• Microbiology
• Genetics
• Pharmacology

Background:

• The emergence of antibiotic resistance in Streptococcus pneumoniae is a significant public health concern.
• Hypermutable bacterial strains can accelerate the development of resistance.
• The role of sub-inhibitory antibiotic concentrations in selecting for hypermutators is not fully understood.

Purpose of the Study:

• To investigate the selection of hypermutable Streptococcus pneumoniae strains by low cefotaxime concentrations.
• To examine the impact of cefotaxime-induced hypermutation on the acquisition of secondary antibiotic resistance.

Main Methods:

• A mixed culture of a hypermutable hexA mutant and its isogenic wild-type Streptococcus pneumoniae strain was exposed to low cefotaxime concentrations.
• Selection and characterization of resistant variants.
• Determination of mutation frequencies for ciprofloxacin resistance in selected strains.

Main Results:

• The hypermutable hexA mutant strain was significantly selected even at very low cefotaxime concentrations.
• All selected variants carried a specific mutation (Thr550-->Ala) in the pbp2x gene.
• Cefotaxime-selected mutants exhibited a 10-fold higher mutation frequency for ciprofloxacin resistance.

Conclusions:

• Sub-lethal cefotaxime concentrations can select for hypermutable Streptococcus pneumoniae.
• Selection of hypermutators by one antibiotic can increase the risk of acquiring resistance to other antibiotics.
• This study models the potential for evolution of multi-drug resistance in bacteria.