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Antimicrobial Agents and Chemotherapy, April 2007, p. 1580-1581, Vol. 51, No. 4
0066-4804/07/$08.00+0     doi:10.1128/AAC.01254-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

LETTER TO THE EDITOR

In Vitro Activity of API-1252, a Novel FabI Inhibitor, against Clinical Isolates of Staphylococcus aureus and Staphylococcus epidermidis

Top Letter References

 
API-1252 (Fig. 1), an inhibitor of bacterial enoyl-acyl carrier protein (enoyl-ACP) reductase (FabI), is being developed by Affinium Pharmaceuticals, Inc. (Toronto, Canada), in both oral and intravenous formulations, for single-agent and combination treatment of antimicrobial-susceptible and -resistant staphylococcal infections, particularly Staphylococcus aureus infections.

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FIG. 1. Chemical structure of API-1252.

To assess the in vitro activity of API-1252 against recent clinical isolates of S. aureus and Staphylococcus epidermidis, we selected 350 isolates of methicillin-susceptible S. aureus (MSSA), 154 isolates of methicillin-resistant S. aureus (MRSA), 50 isolates of methicillin-susceptible S. epidermidis (MSSE), and 50 isolates of methicillin-resistant S. epidermidis (MRSE) collected from May 2005 to June 2006 as part of an ongoing 19-center national surveillance study, the Canadian Intensive Care Unit study. Clinical and Laboratory Standards Institute (CLSI)-specified broth microdilution testing was performed using frozen panels (prepared in-house) containing API-1252, ciprofloxacin, gentamicin, oxacillin, and vancomycin (2, 6). API-1252 was tested over a doubling dilution concentration range from 0.001 to 2 µg/ml, and its MICs were read following 20 to 24 h of incubation at 35°C in ambient air (2). The reference strains S. aureus ATCC 29213 and S. aureus ATCC 33592 (MRSA) reproducibly demonstrated MICs to API-1252 of 0.015 and 0.008 µg/ml, respectively. The methicillin-resistant phenotype of each isolate of staphylococci was confirmed using a 30-µg cefoxitin disk (2). MICs for ciprofloxacin, gentamicin, oxacillin, and vancomycin were interpreted using CLSI M100-S15 guidelines (2).

The genotypes of isolates of MRSA were established using a previously described mecA and nuc multiplex PCR assay (5), and each isolate of MRSA was subtyped using a standardized, previously described pulsed-field gel electrophoresis (PFGE) protocol (4, 5, 9). MRSA isolates identified by PFGE profile as community-acquired strains (i.e., CMRSA-7 [USA-400]; CMRSA-10 [USA-300]) were tested by PCR to detect lukF-PV, lukS-PV, eta, and etb toxin genes (5), and their staphylococcal chromosome cassette mec type was determined, as previously described (7).

Table 1 depicts the concentrations of API-1252 that inhibited 50% (MIC₅₀) and 90% (MIC₉₀s) of isolates and MIC ranges. The MIC₉₀s of API-1252 for MSSA and MRSA were 0.015 µg/ml; all isolates of S. aureus were inhibited by API-1252 at a concentration of 0.125 µg/ml. No difference in API-1252 in vitro activity was observed for hospital-associated and community-associated isolates of MRSA. The MIC₉₀s of API-1252 for MSSE and MRSE were 0.06 and 0.03 µg/ml, respectively; all isolates of S. epidermidis were inhibited by API-1252 at a concentration of 0.5 µg/ml.

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TABLE 1. Activity of API-1252 against staphylococci with various phenotypic and genotypic profiles

FabI is an essential enzyme that catalyzes the reduction of trans-2-enoyl-ACP to acyl-ACP in the final step of each elongation cycle in bacterial fatty acid biosynthesis (3, 8). FabI is a selective antibacterial target for S. aureus and S. epidermidis, as well as for Haemophilus influenzae, Moraxella catarrhalis, and Escherichia coli; it is the sole enoyl-ACP reductase present in each of these bacterial species (8). No alternative enzyme or rescue pathway has been identified for FabI in staphylococci, suggesting that resistance to FabI inhibitors, such as API-1252, will not readily emerge with therapy (1).

In conclusion, API-1252 demonstrated potent in vitro activity against recent clinical isolates of MSSA and MRSA (MIC₉₀, 0.015 µg/ml), MSSE (MIC₉₀, 0.06 µg/ml), and MRSE (MIC₉₀, 0.03 µg/ml) from patients with serious hospital infections. API-1252 is a potentially promising advance in the treatment of patients with staphylococcal infections known or suspected to be resistant to conventional therapies both in hospitals and in the community.

 
We thank the investigators and laboratory site staff at each medical center that participated in the Canadian Intensive Care Unit (CAN-ICU) study. The Canadian medical centers and investigators (shown in the parentheses) were as follows: Royal University Hospital, Saskatoon, Saskatchewan (J. Blondeau); Children's Hospital of Eastern Ontario, Ottawa, Ontario (F. Chan); Queen Elizabeth II Health Sciences Centre and Dartmouth General/Izaak Walton Killam Health Centre, Halifax, Nova Scotia (R. Davidson); St. Boniface General Hospital, Winnipeg, Manitoba (G. Harding); Health Sciences Centre, Winnipeg, Manitoba (D. Hoban); London Health Sciences Centre, London, Ontario (Z. Hussain); Victoria General Hospital, Victoria, British Columbia (P. Kibsey); South East Health Care Corp., Moncton, New Brunswick (M. Kuhn); Hôpital Maisonneuve-Rosemont, Montreal, Quebec (M. Laverdière); St. Joseph's Hospital, Hamilton, Ontario (C. Lee); Montreal General Hospital, Montreal, Quebec (V. Loo); Mount Sinai Hospital, Toronto, Ontario (S. Poutanen); Hamilton Health Sciences Centre, McMaster Site, Hamilton, Ontario (C. Main); Cape Breton Regional Hospital, Sydney, Nova Scotia (K. McVarnish); University of Alberta Hospitals, Edmonton, Alberta (R. Rennie); Vancouver Hospital, Vancouver, British Columbia (D. Roscoe); Regina General Hospital, Regina, Saskatchewan (E. Thomas); and St. John Regional Hospital, St. John, New Brunswick (Y. Yaschuk). We also thank M. DeCorby and C. Siemens for their technical assistance in the completion of this testing.

The study was financially supported in part by Affinium Pharmaceuticals, Inc. (Toronto, Ontario, Canada).

 
Published ahead of print on 12 January 2007.

Top Letter References

 

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						James A. Karlowsky* Department of Clinical Microbiology Health Sciences Centre/Diagnostic Services of Manitoba Health Sciences Centre, MS673C 820 Sherbrook Street Winnipeg, Manitoba R3A 1R9, Canada Nancy M. Laing Trish Baudry Department of Medical Microbiology and Infectious Diseases Faculty of Medicine University of Manitoba Winnipeg, Manitoba, Canada Nachum Kaplan David Vaughan Affinium Pharmaceuticals, Inc. Toronto, Ontario, Canada Daryl J. Hoban Department of Clinical Microbiology Health Sciences Centre/Diagnostic Services of Manitoba Winnipeg, Manitoba, Canada George G. Zhanel Department of Medical Microbiology and Infectious Diseases Faculty of Medicine University of Manitoba Winnipeg, Manitoba, Canada
						* Phone: (204) 787-4597,Fax: (204) 787-4699,E-mail: jkarlowsky{at}hsc.mb.ca

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Antimicrobial Agents and Chemotherapy, April 2007, p. 1580-1581, Vol. 51, No. 4
0066-4804/07/$08.00+0     doi:10.1128/AAC.01254-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Karlowsky, J. A., Kaplan, N., Hafkin, B., Hoban, D. J., Zhanel, G. G. (2009). AFN-1252, a FabI Inhibitor, Demonstrates a Staphylococcus-Specific Spectrum of Activity. Antimicrob. Agents Chemother. 53: 3544-3548 [Abstract] [Full Text]  

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