Twenty-five serial passages of Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus and 50 passages of methicillin-resistant Staphylococcus aureus resulted in no significant increase in NVC-422 MICs, while ciprofloxacin MICs increased 256-fold for E. coli and 32-fold for P. aeruginosa and S. aureus. Mupirocin, fusidic acid, and retapamulin MICs for MRSA increased 64-, 256-, and 16-fold, respectively. No cross-resistance to NVC-422 was observed with mupirocin-, fusidic acid-, and retapamulin-resistant strains. Multiple-passage studies determine the effect of selective pressure of antibiotics on microorganisms (15), resulting in cumulative acquisition of mutations at the genetic level (3,5,6,13). The development of resistance is a result of the frequency of mutation, the number and type of mutations required to express resistance, the potency and concentration of the treating drug, and other factors (9,10,14). Currently, there is an unmet medical need for novel antimicrobial agents that are effective against resistant pathogens (14, 18).NVC-422 (N,N-dichloro-2,2-dimethyltaurine) (20) is active against Gram-positive and Gram-negative bacteria (including drug-resistant pathogens), fungi, and viruses (21). NVC-422 mechanism-of-action studies (22) indicate that it kills microorganisms by inactivating proteins via oxidative modification of Met and Cys. This mechanism differentiates NVC-422 from antibiotics by attacking multiple targets, thereby making it highly unlikely for microorganisms to develop resistance.NVC-422 is currently in clinical development for impetigo, urinary catheter blockage and encrustation, and adenoviral conjunctivitis.In this study, we investigated the propensity of NVC-422 to select for resistance by passaging bacteria at subinhibitory concentrations. Representative organisms Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and methicillin-resistant S. aureus (MRSA) were selected (1,3,12,17). Ciprofloxacin was selected as a broad-spectrum comparator. Mupirocin, fusidic acid, and retapamulin were selected as comparators against MRSA, as these antibiotics are used for the treatment of topical infections (6,18,19).The synthesis of NVC-422 has been described previously (20). The purity of NVC-422 was 99.83% by high-performance liquid chromatography (HPLC). The stabilities of NVC-422 (100 g/ ml) in cation-adjusted Mueller-Hinton broth (CAMHB) and M9 minimal medium were tested at 37°C using the Agilent HPLC-1200 system (Agilent Technologies, Palo Alto, CA) with a diode array UV detector.E. coli ATCC 25922, S. aureus ATCC 29213, and MRSA ATCC 33591 were purchased from the American Type Culture Collection (ATCC, Manassas, VA); P. aeruginosa PAO1 was obtained from Queen's University (Kingston, Ontario, Canada). All strains were grown on tryptic soy agar (Difco Laboratories, Detroit, MI) at 37°C. Antibiotics were obtained from MP Biomedical (Santa Ana, CA), Sigma-Aldrich (St. Louis, MO), and APAC Pharmaceuticals, LLC (Columbia, MD).Determination of MICs was in accordance wit...

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