Abstract:
:Lantibiotics such as nisin (NIS) are peptide antibiotics that may have a role in the chemotherapy of bacterial infections. A perceived benefit of lantibiotics for clinical use is their low propensity to select resistance, although detailed resistance studies with relevant bacterial pathogens are lacking. Here we examined the development of resistance to NIS in Staphylococcus aureus, establishing that mutants, including small-colony variants, exhibiting substantial (4- to 32-fold) reductions in NIS susceptibility could be selected readily. Comparative genome sequencing of a single NISr mutant exhibiting a 32-fold increase in NIS MIC revealed the presence of only two mutations, leading to the substitutions V229G in the purine operon repressor, PurR, and A208E in an uncharacterized protein encoded by SAOUHSC_02955. Independently selected NISr mutants also harbored mutations in the genes encoding these products. Reintroduction of these mutations into the S. aureus chromosome alone and in combination revealed that SAOUHSC_02955(A208E) made the primary contribution to the resistance phenotype, conferring up to a 16-fold decrease in NIS susceptibility. Bioinformatic analyses suggested that this gene encodes a sensor histidine kinase, leading us to designate it "nisin susceptibility-associated sensor (nsaS)." Doubling-time determinations and mixed-culture competition assays between NISr and NISs strains indicated that NIS resistance had little impact on bacterial fitness, and resistance was stable in the absence of selection. The apparent ease with which S. aureus can develop and maintain NIS resistance in vitro suggests that resistance to NIS and other lantibiotics with similar modes of action would arise in the clinic if these agents are employed as chemotherapeutic drugs.
journal_name
Antimicrob Agents Chemotherjournal_title
Antimicrobial agents and chemotherapyauthors
Blake KL,Randall CP,O'Neill AJdoi
10.1128/AAC.01077-10subject
Has Abstractpub_date
2011-05-01 00:00:00pages
2362-8issue
5eissn
0066-4804issn
1098-6596pii
AAC.01077-10journal_volume
55pub_type
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