Daptomycin Resistant Mutants

For many antibiotics, the mechanism of antibiotic resistance can help establish the mechanism of action. Therefore, it may be instructive to determine the mechanism(s) of daptomycin resistance to see if it yields insights into the mechanism of action. The incidence of reduced susceptibility to daptomycin in clinical isolates is very low and resistant strains are usually associated with deep-seated infections in compromised patients.2,9,36,37 

The level of LPG also influences the susceptibility of an MRSA strain to other antibiotics. A transposition mutant defective in mprF was less susceptible to moenomycin, but more susceptible to oxacillin, methicillin and gentamicin.41 Recent studies have shown that DapR strains have increased ratios of LPG/ PG,42 or increased amounts of LPG in the outer leaflet of the membrane, thus increasing the surface positive charge.43 This indicates that the mutations have enhanced ability to couple lysine to PG or to flip LPG to the outer leaflet. Deletion of mprF increases susceptibility to daptomycin by about four-fold in S. aureus.43,44 Disruption of mprF in B. subtilis caused a two-fold reduction in daptomycin MIC.34 

These combined results support the idea that Ca++-bound daptomycin functions as a cationic peptide 28,29 thus the increased positive charge imparted 

The mutations in rpoB and rpoC in DapR S. aureus strains may alter the patterns of transcription, thus influencing membrane composition or key target protein levels associated with the dual mechanism of action. 

Daptomycin localises to the cell division septum in B. subtilis 34 it causes rapid cell death without lysis,48 causes the formation of aberrant cell wall septa48 and treats biofilms effectively in S. aureus. 9 Daptomycin induces the cell wall stress stimulon in S. aureus and B. subtilis,30 34 but has very poor activity (MIC of 128) against an E. coli imp mutant defective in outer membrane assembly,5 whereas vancomycin, another bulky peptide that normally does not penetrate the outer membrane, has an MIC of 0.8 against E. coli imp.50 

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