title: Investigation of the potential for mutational resistance to XF-73, retapamulin, mupirocin, fusidic acid, daptomycin, and vancomycin in methicillin-resistant Staphylococcus aureus isolates during a 55-passage study.
abstract: XF-73 is a dicationic porphyrin drug with rapid Gram-positive antibacterial activity currently undergoing clinical trials for the nasal decolonization of Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA). In multistep (55-passage) resistance selection studies in the presence of subinhibitory concentrations of XF-73, retapamulin, mupirocin, fusidic acid, and vancomycin against four Network on Antimicrobial Resistance in Staphylococcus aureus MRSA strains, there was no >4-fold increase in the MIC for XF-73 after 55 passages. In contrast, there was an increase in the MICs for retapamulin (from 0.25 μg/ml to 4 to 8 μg/ml), for mupirocin (from 0.12 μg/ml to 16 to 512 μg/ml), for fusidic acid (from 0.12 μg/ml to 256 μg/ml), and for vancomycin (from 1 μg/ml to 8 μg/ml in two of the four strains tested). Further investigations using S. aureus NRS384 (USA300) and daptomycin demonstrated a 64-fold increase in the MIC after 55 passages (from 0.5 μg/ml to 32 μg/ml) with a >4-fold increase in the MIC obtained after only five passages. Sequencing analysis of selected isolates confirmed previously reported point mutations associated with daptomycin resistance. No cross-resistance to XF-73 was observed with the daptomycin-resistant strains, suggesting that whereas the two drugs act on the bacterial cell membrane, their specific site of action differs. XF-73 thus represents the first in a new class of antibacterial drugs, which (unlike the comparator antibiotics) after 55 passages exhibited a ≤4-fold increase in MIC against the strains tested. Antibacterial drugs with a low propensity for inducing bacterial resistance are much needed for the prevention and treatment of multidrug-resistant bacteria both within and outside the hospital setting.
authors.affiliation: Quotient Bioresearch Limited, Newmarket Road, Fordham, Cambs CB75WW, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Farrell
authors.forename: Marion
authors.initials: M
authors.lastname: Robbins
authors.forename: William
authors.initials: W
authors.lastname: Rhys-Williams
authors.forename: William G
authors.initials: WG
authors.lastname: Love
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D017576:Daptomycin / Q000494:pharmacology*; D004224:Diterpenes; D005672:Fusidic Acid / Q000494:pharmacology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D016712:Mupirocin / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011166:Porphyrins / Q000737:chemistry / Q000494:pharmacology*; D017422:Sequence Analysis, DNA; D014640:Vancomycin / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004224:Diterpenes; D011166:Porphyrins; C521987:XF73 compound; C508887:retapamulin; D005672:Fusidic Acid; D014640:Vancomycin; D016712:Mupirocin; D017576:Daptomycin