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With the increasing spread of methicillin-resistant  Staphylococcus aureus  worldwide, fosfomycin has begun to be used more often, either alone or in combination with other antibiotics, for treating methicillin-resistant  S. aureus  infections, resulting in the emergence of fosfomycin-resistant strains. Fosfomycin resistance is reported to be mediated by fosfomycin-modifying enzymes (FosA, FosB, FosC, and FosX) and mutations of the target enzyme MurA or the membrane transporter proteins UhpT and GlpT. Our previous studies indicated that the  fos  genes might not the major fosfomycin resistance mechanism in  S. aureus , whereas mutations of  glpT  and  uhpT  seemed to be more related to fosfomycin resistance. However, the precise role of these two genes in  S. aureus  fosfomycin resistance remains unclear. The aim of the present study was to investigate the role of  glpT  and  uhpT  in  S. aureus  fosfomycin resistance. Homologous recombination was used to knockout the  uhpT  and  glpT  genes in  S. aureus  Newman. Gene complementation was generated by the plasmid pRB473 carrying these two genes. The fosfomycin minimal inhibitory concentration (MIC) of the strains was measured by the  E -test to observe the influence of gene deletion on antibiotic susceptibility. In addition, growth curves were constructed to determine whether the mutations have a significant influence on bacterial growth. Deletion of  uhpT, glpT , and both of them led to increased fosfomycin MIC 0.5 μg/ml to 32 μg/ml, 4 μg/ml, and >1024 μg/ml, respectively. By complementing  uhpT  and  glpT  into the deletion mutants, the fosfomycin MIC decreased from 32 to 0.5 μg/ml and from 4 to 0.25 μg/ml, respectively. Moreover, the transporter gene-deleted strains showed no obvious difference in growth curves compared to the parental strain. In summary, our study strongly suggests that mutations of  uhpT  and  glpT  lead to fosfomycin resistance in  S. aureus , and that  uhpT  mutation may play a more important role. The high resistance and low biological fitness cost resulting from  uhpT  and  glpT  deletion suggest that these strains might have an evolutionary advantage in a fosfomycin-rich clinical situation, which should be closely monitored.

Mutations of the Transporter Proteins GlpT and UhpT Confer Fosfomycin Resistance in Staphylococcus aureus