Abstract
AFN-1252, a potent inhibitor of enoyl-acyl carrier protein reductase (FabI), inhibited all clinical isolates of Staphylococcus aureus (n = 502) and Staphylococcus epidermidis (n = 51) tested, including methicillin (meticillin)-resistant isolates, at concentrations of ≤0.12 μg/ml. In contrast, AFN-1252 was inactive (MIC90, >4 μg/ml) against clinical isolates of Streptococcus pneumoniae, beta-hemolytic streptococci, Enterococcus spp., Enterobacteriaceae, nonfermentative gram-negative bacilli, and Moraxella catarrhalis. These data support the continued development of AFN-1252 for the treatment of patients with resistant staphylococcal infections.
AFN-1252 is an investigational inhibitor of staphylococcal FabI, an essential enzyme that catalyzes the reduction of trans-2-enoyl-acyl carrier protein (trans-2-enoyl-ACP) to acyl-ACP, the final step in each elongation cycle of bacterial fatty acid biosynthesis (1, 7, 10). Enoyl-ACP reductase is known to have four distinct enzyme forms: FabI, FabK, FabL, and FabV (8). FabI is the sole form of enoyl-ACP reductase present in Staphylococcus aureus, Staphylococcus epidermidis, and a few other bacterial species (6, 8, 9). No alternative enzyme or rescue pathway for FabI in staphylococci has been identified, suggesting that FabI is essential to Staphylococcus cell viability and that resistance to FabI inhibitors such as AFN-1252 will not readily emerge with therapy (1).
AFN-1252 is being developed by Affinium Pharmaceuticals, Inc. (Toronto, Canada), in both oral and intravenous formulations, for the treatment of antimicrobial-susceptible and -resistant staphylococcal infections, particularly infections caused by S. aureus. The structure of AFN-1252 has been described previously (9). AFN-1252 has demonstrated in vivo efficacy in a murine subcutaneous abscess model using a strain of methicillin (meticillin)-resistant S. aureus (12). The present study was undertaken to assess the in vitro activities of AFN-1252 against recent clinical isolates of staphylococci, as well as other gram-positive cocci and gram-negative bacilli, to demonstrate the full antibacterial spectrum of activity of AFN-1252.
Clinically relevant isolates were collected at 12 Canadian hospital laboratories from January to December 2007 as a part of the ongoing CANWARD in vitro surveillance study and shipped to the coordinating laboratory (Health Sciences Centre, Winnipeg, Canada) for identity confirmation and antimicrobial susceptibility testing. Multidrug-resistant staphylococci were defined as those isolates that were resistant to two or more of the agents ciprofloxacin, clindamycin, and gentamicin and included both methicillin-susceptible and methicillin-resistant isolates. Vancomycin-intermediate S. aureus and vancomycin-resistant S. aureus isolates were obtained through the Network on Antimicrobial Resistance in Staphylococcus aureus program (supported under NIAID, NIH, contract no. N01-AI-95359) for testing against AFN-1252.
Clinical and Laboratory Standards Institute (CLSI)-specified broth microdilution testing was performed using frozen, in-house-prepared, 96-well panels containing AFN-1252 and comparative agents (3). Dimethyl sulfoxide was used as the solvent and diluent for AFN-1252. AFN-1252 was tested over a doubling-dilution concentration range of 0.008 to 4 μg/ml, and its MICs were recorded following 20 to 24 h of incubation at 35°C in ambient air. MICs were interpreted using CLSI M100-S17 guidelines (2). For the reference strain S. aureus ATCC 29213, AFN-1252 reproducibly demonstrated an MIC of 0.015 μg/ml.
AFN-1252 inhibited all isolates of methicillin-susceptible and methicillin-resistant S. aureus and S. epidermidis at concentrations of ≤0.12 μg/ml (Table 1). AFN-1252 demonstrated MIC90s for methicillin-resistant S. aureus and S. epidermidis and multidrug-resistant S. aureus and S. epidermidis (data not shown) of ≤0.008 μg/ml. AFN-1252 was less active in vitro against vancomycin-intermediate S. aureus isolates (n = 12; MIC90, 0.12 μg/ml) and vancomycin-resistant S. aureus isolates (n = 12; MIC90, 0.06 μg/ml) than against vancomycin-susceptible isolates (MIC90, ≤0.008 μg/ml) (data not shown). AFN-1252 was inactive (MIC range, 4 to >4 μg/ml) against nonstaphylococcal gram-positive pathogens and gram-negative pathogens (Table 1).
TABLE 1.
Activities of AFN-1252 and comparator agents against staphylococci, nonstaphylococcal gram-positive pathogens, and gram-negative pathogens
| Species or isolate group (no. of isolates) | Agent | MIC (μg/ml)
|
% of isolates classified by MIC as:
|
||||
|---|---|---|---|---|---|---|---|
| 50% | 90% | Range | Susceptible | Intermediate | Resistant | ||
| Methicillin-susceptible S. aureus (375) | AFN-1252 | ≤0.008 | ≤0.008 | ≤0.008-0.12 | |||
| Cefazolin | ≤0.5 | 1 | ≤0.5-8 | 100 | 0 | 0 | |
| Ciprofloxacin | 0.5 | 8 | ≤0.06->16 | 83.8 | 4.2 | 12.0 | |
| Clindamycin | ≤0.12 | ≤0.12 | ≤0.12->8 | 91.0 | 0.4 | 8.6 | |
| Gentamicin | ≤0.5 | 1 | ≤0.5->32 | 96.7 | 0.1 | 3.2 | |
| Linezolid | 2 | 2 | ≤0.12-4 | 100 | 0 | 0 | |
| Trimethoprim-sulfamethoxazole | ≤0.12 | ≤0.12 | ≤0.12->8 | 99.3 | 0.7 | ||
| Vancomycin | 1 | 1 | ≤0.25-2 | 100 | 0 | 0 | |
| Methicillin-resistant S. aureus (127) | AFN-1252 | ≤0.008 | ≤0.008 | ≤0.008-0.06 | |||
| Cefazolin | 64 | >128 | 32->128 | 0 | 0 | 100 | |
| Ciprofloxacin | >16 | >16 | 0.25->16 | 10.1 | 0.3 | 89.6 | |
| Clindamycin | >8 | >8 | ≤0.12->8 | 37.9 | 0.3 | 61.8 | |
| Gentamicin | ≤0.5 | >32 | ≤0.5->32 | 86.8 | 0 | 13.2 | |
| Linezolid | 2 | 4 | 0.25-4 | 100 | 0 | 0 | |
| Trimethoprim-sulfamethoxazole | ≤0.12 | 8 | ≤0.12->8 | 87.8 | 12.2 | ||
| Vancomycin | 1 | 1 | ≤0.25-2 | 100 | 0 | 0 | |
| Methicillin-susceptible S. epidermidis (42) | AFN-1252 | ≤0.008 | 0.03 | ≤0.008-0.06 | |||
| Cefazolin | 1 | 4 | ≤0.5-8 | 100 | 0 | 0 | |
| Ciprofloxacin | 4 | >16 | ≤0.06->16 | 47.2 | 0 | 52.8 | |
| Clindamycin | ≤0.12 | >8 | ≤0.12->8 | 61.1 | 0 | 38.9 | |
| Gentamicin | ≤0.5 | >32 | ≤0.5->32 | 58.3 | 10.2 | 31.5 | |
| Linezolid | 0.5 | 1 | ≤0.12-2 | 100 | 0 | 0 | |
| Trimethoprim-sulfamethoxazole | 1 | >8 | ≤0.12->8 | 58.3 | 41.7 | ||
| Vancomycin | 1 | 2 | ≤0.25-2 | 100 | 0 | 0 | |
| Methicillin-resistant S. epidermidis (9) | AFN-1252 | ≤0.008 | ≤0.008 | ≤0.008 | |||
| Cefazolin | 64 | 128 | 32-128 | 0 | 0 | 100 | |
| Ciprofloxacin | >16 | >16 | 8->16 | 0 | 0 | 100 | |
| Clindamycin | >8 | >8 | ≤0.12->8 | 10.0 | 0 | 90.0 | |
| Gentamicin | 16 | >32 | ≤0.5->32 | 30.0 | 15.0 | 55.0 | |
| Linezolid | 1 | 1 | 0.5-1 | 100 | 0 | 0 | |
| Trimethoprim-sulfamethoxazole | 4 | 8 | ≤0.12->8 | 25.0 | 75.0 | ||
| Vancomycin | 1 | 2 | 1-2 | 100 | 0 | 0 | |
| Streptococcus pneumoniae (489) | AFN-1252 | >4 | >4 | 4->4 | |||
| Penicillin | 0.06 | 0.25 | ≤0.03->8 | 79.3 | 15.7 | 5.0 | |
| Levofloxacin | 0.5 | 1 | ≤0.06-32 | 99.4 | 0 | 0.6 | |
| Ceftriaxone | ≤0.06 | 0.12 | ≤0.06-4 | 99.7 | 0.2 | 0.1 | |
| Linezolid | 0.5 | 1 | ≤0.12-2 | 100 | |||
| Trimethoprim-sulfamethoxazole | ≤0.12 | 1 | ≤0.12->8 | 86.3 | 6.7 | 7.0 | |
| Vancomycin | ≤0.25 | ≤0.25 | ≤0.25-0.5 | 100 | |||
| Streptococcus pyogenes (73) | AFN-1252 | >4 | >4 | >4 | |||
| Penicillin | ≤0.03 | ≤0.03 | ≤0.03-0.12 | 100 | |||
| Ciprofloxacin | 1 | 2 | 0.25-4 | ||||
| Clindamycin | ≤0.06 | ≤0.06 | ≤0.06->8 | 97.3 | 0 | 2.7 | |
| Linezolid | 1 | 1 | 0.5-2 | 100 | |||
| Trimethoprim-sulfamethoxazole | ≤0.12 | ≤0.12 | ≤0.12-0.25 | ||||
| Vancomycin | 0.5 | 0.5 | ≤0.25-0.5 | 100 | |||
| Streptococcus agalactiae (86) | AFN-1252 | >4 | >4 | >4 | |||
| Penicillin | 0.06 | 0.25 | ≤0.03-0.12 | 100 | |||
| Ciprofloxacin | 1 | 2 | 0.5->16 | ||||
| Clindamycin | ≤0.06 | >8 | ≤0.06->8 | 85.2 | 2.3 | 12.5 | |
| Linezolid | 1 | 1 | ≤0.12-2 | 100 | |||
| Trimethoprim-sulfamethoxazole | ≤0.12 | ≤0.12 | ≤0.12-0.25 | ||||
| Vancomycin | ≤0.25 | ≤0.25 | ≤0.25-0.5 | 100 | |||
| Enterococcus faecalis (81) | AFN-1252 | >4 | >4 | >4 | |||
| Cefazolin | 32 | 128 | 0.5->128 | ||||
| Ciprofloxacin | 2 | >16 | 0.25->16 | 38.3 | 26.6 | 35.1 | |
| Clindamycin | >8 | >8 | ≤0.12->8 | ||||
| Linezolid | 2 | 2 | 0.5-4 | 98.7 | 1.3 | 0 | |
| Trimethoprim-sulfamethoxazole | ≤0.12 | 0.25 | ≤0.12->8 | ||||
| Vancomycin | 1 | 2 | 0.5-4 | 100 | 0 | 0 | |
| Enterococcus faecium (38) | AFN-1252 | >4 | >4 | 4->4 | |||
| Cefazolin | >128 | >128 | 32->128 | ||||
| Ciprofloxacin | >16 | >16 | 1->16 | 12.1 | 5.2 | 82.7 | |
| Clindamycin | >8 | >8 | ≤0.12->8 | ||||
| Linezolid | 2 | 2 | 1-4 | 91.4 | 8.6 | 0 | |
| Trimethoprim-sulfamethoxazole | ≤0.12 | >8 | ≤0.12->8 | ||||
| Vancomycin | 0.5 | >32 | ≤0.25->32 | 87.9 | 0 | 12.1 | |
| E. coli (599) | AFN-1252 | 4 | >4 | 0.5->4 | |||
| Cefazolin | 2 | 64 | ≤0.5->128 | 82.1 | 3.8 | 14.1 | |
| Ciprofloxacin | ≤0.06 | >16 | ≤0.06->16 | 75.2 | 0.3 | 24.5 | |
| Gentamicin | ≤0.5 | 16 | ≤0.5->32 | 88.9 | 0.5 | 10.6 | |
| Meropenem | ≤0.06 | ≤0.06 | ≤0.06-0.5 | 100 | 0 | 0 | |
| Piperacillin-tazobactam | 2 | 4 | ≤1->512 | 97.6 | 1.0 | 1.4 | |
| Trimethoprim-sulfamethoxazole | ≤0.12 | >8 | ≤0.12->8 | 73.4 | 26.6 | ||
| K. pneumoniae (199) | AFN-1252 | >4 | >4 | 2->4 | |||
| Cefazolin | 2 | 8 | ≤0.5->128 | 91.4 | 1.8 | 6.8 | |
| Ciprofloxacin | ≤0.06 | 0.5 | ≤0.06->16 | 92.5 | 0.9 | 6.6 | |
| Gentamicin | ≤0.5 | ≤0.5 | ≤0.5->32 | 96.7 | 0.4 | 2.9 | |
| Meropenem | ≤0.06 | ≤0.06 | ≤0.06-0.25 | 100 | 0 | 0 | |
| Piperacillin-tazobactam | 2 | 8 | ≤1->512 | 96.7 | 1.3 | 2.0 | |
| Trimethoprim-sulfamethoxazole | ≤0.12 | 1 | ≤0.12->8 | 91.4 | 8.6 | ||
| Klebsiella oxytoca (32) | AFN-1252 | >4 | >4 | 2->4 | |||
| Cefazolin | 8 | 32 | ≤0.5->128 | 60.0 | 23.0 | 17.0 | |
| Ciprofloxacin | ≤0.06 | 0.12 | ≤0.06->16 | 95.0 | 2.0 | 3.0 | |
| Gentamicin | ≤0.5 | ≤0.5 | ≤0.5->32 | 97.0 | 2.0 | 1.0 | |
| Meropenem | ≤0.06 | ≤0.06 | ≤0.06-0.12 | 100 | 0 | 0 | |
| Piperacillin-tazobactam | 2 | 16 | ≤1->512 | 90.0 | 1.0 | 9.0 | |
| Trimethoprim-sulfamethoxazole | ≤0.12 | ≤0.12 | ≤0.12->8 | 95.0 | 5.0 | ||
| Enterobacter cloacae (72) | AFN-1252 | >4 | >4 | 4->4 | |||
| Cefazolin | 128 | >128 | 1->128 | 5.4 | 3.6 | 91.0 | |
| Ciprofloxacin | ≤0.06 | 0.5 | ≤0.06->16 | 91.6 | 0.6 | 7.8 | |
| Gentamicin | ≤0.5 | 1 | ≤0.5->32 | 96.4 | 0 | 3.6 | |
| Meropenem | ≤0.06 | ≤0.06 | ≤0.06-0.5 | 100 | 0 | 0 | |
| Piperacillin-tazobactam | 2 | 64 | ≤1->512 | 82.6 | 8.4 | 9.0 | |
| Trimethoprim-sulfamethoxazole | ≤0.12 | 1 | ≤0.12->8 | 91.6 | 8.4 | ||
| Proteus mirabilis (34) | AFN-1252 | 4 | >4 | 2->4 | |||
| Cefazolin | 8 | 16 | 1-64 | 86.6 | 8.4 | 5.0 | |
| Ciprofloxacin | ≤0.06 | 2 | ≤0.06->16 | 82.4 | 8.4 | 9.2 | |
| Gentamicin | 1 | 2 | ≤0.5->32 | 95.8 | 0.8 | 3.4 | |
| Meropenem | ≤0.06 | ≤0.06 | ≤0.06-0.25 | 100 | 0 | 0 | |
| Piperacillin-tazobactam | 2 | 64 | ≤1-2 | 100 | 0 | 0 | |
| Trimethoprim-sulfamethoxazole | ≤0.12 | 2 | ≤0.12->8 | 90.8 | 9.2 | ||
| Serratia marcescens (39) | AFN-1252 | 4 | >4 | 2->4 | |||
| Cefazolin | >128 | >128 | 2->128 | 0.9 | 0 | 99.1 | |
| Ciprofloxacin | 0.12 | 2 | ≤0.06-16 | 88.8 | 3.7 | 7.5 | |
| Gentamicin | ≤0.5 | 1 | ≤0.5->32 | 91.6 | 3.7 | 4.7 | |
| Meropenem | ≤0.06 | ≤0.06 | ≤0.06-2 | 100 | 0 | 0 | |
| Piperacillin-tazobactam | 2 | 8 | ≤1-128 | 94.4 | 4.7 | 0.9 | |
| Trimethoprim-sulfamethoxazole | 0.5 | 1 | ≤0.12-8 | 97.2 | 2.8 | ||
| Pseudomonas aeruginosa (137) | AFN-1252 | >4 | >4 | >4 | |||
| Cefazolin | >128 | >128 | 16->128 | ||||
| Ciprofloxacin | 0.5 | 16 | ≤0.06->16 | 66.0 | 11.0 | 23.4 | |
| Gentamicin | 4 | >32 | ≤0.5->32 | 60.1 | 19.0 | 20.9 | |
| Meropenem | 0.5 | 8 | ≤0.06->64 | 87.8 | 4.1 | 8.1 | |
| Piperacillin-tazobactam | 4 | 64 | ≤1->512 | 92.7 | 0 | 7.3 | |
| Trimethoprim-sulfamethoxazole | >8 | >8 | ≤0.12->8 | 14.5 | 85.5 | ||
| Stenotrophomonas maltophilia (26) | AFN-1252 | >4 | >4 | >4 | |||
| Cefazolin | >128 | >128 | 128->128 | ||||
| Ciprofloxacin | 4 | >16 | ≤0.06->16 | ||||
| Gentamicin | 32 | >32 | ≤0.5->32 | ||||
| Meropenem | >64 | >64 | ≤0.06->64 | ||||
| Piperacillin-tazobactam | >512 | 16->512 | |||||
| Trimethoprim-sulfamethoxazole | 1 | >8 | ≤0.12->8 | 75.5 | 24.5 | ||
| Acinetobacter baumannii (15) | AFN-1252 | >4 | >4 | >4 | |||
| Cefazolin | >128 | >128 | 64->128 | ||||
| Ciprofloxacin | 0.25 | 4 | 0.12->16 | 88.0 | 0 | 12.0 | |
| Gentamicin | ≤0.5 | 1 | ≤0.5->32 | 92.0 | 0 | 8.0 | |
| Meropenem | 0.5 | 4 | ≤0.06-32 | 92.0 | 0 | 8.0 | |
| Piperacillin-tazobactam | 4 | >512 | ≤1->512 | 76.0 | 12.0 | 12.0 | |
| Trimethoprim-sulfamethoxazole | ≤0.12 | >8 | ≤0.12->8 | 84.0 | 16.0 | ||
| M. catarrhalis (70) | AFN-1252 | >4 | >4 | 2->4 | |||
| Penicillin | >8 | >8 | ≤0.03->8 | ||||
| Ciprofloxacin | ≤0.06 | ≤0.06 | ≤0.06 | 100 | |||
| Gentamicin | ≤0.5 | ≤0.5 | ≤0.5 | ||||
| Meropenem | ≤0.06 | ≤0.06 | ≤0.06 | ||||
| Piperacillin-tazobactam | ≤1 | ≤1 | ≤1 | ||||
| Trimethoprim-sulfamethoxazole | ≤0.12 | 0.5 | ≤0.12-1 | 94.0 | 6.0 | 0 | |
In this study, AFN-1252 demonstrated narrow-spectrum, staphylococcus-specific in vitro activity and was inactive against all nonstaphylococcal potential human pathogens tested, including streptococci, enterococci, species of Enterobacteriaceae, nonfermentative gram-negative bacilli, and Moraxella catarrhalis. AFN-1252's narrow-spectrum, staphylococcus-specific activity may be an attractive attribute for the treatment of patients with staphylococcal infections or the decolonization of patients with methicillin-resistant S. aureus because, compared to other treatment agents, it has a reduced risk of selecting for resistance in normal flora and other colonizing bacterial species and a reduced risk of altering normal flora and will potentially contribute minimally to the overall burden of resistance intrinsic with broad-spectrum agents.
Only one previously published study has described the in vitro activity of AFN-1252 (9). In that study, all 350 isolates of methicillin-susceptible and 154 isolates of methicillin-resistant S. aureus were inhibited by concentrations of AFN-1252 of ≤0.12 μg/ml, results identical to the data presented in this study (Table 1). All methicillin-susceptible (n = 50) and methicillin-resistant (n = 50) S. epidermidis isolates were inhibited by concentrations of AFN-1252 of ≤0.5 μg/ml (MIC90s, 0.03 to 0.06 μg/ml) (9), two doubling dilutions higher than those reported in the present study (Table 1). AFN-1252 has been reported to be inactive in vitro against gram-positive anaerobes, including Bifidobacterium spp., Clostridium perfringens, Clostridium difficile, Eubacterium lentum, Lactobacillus spp., Peptostreptococcus spp., and Propionibacterium acnes, as well as gram-negative anaerobes, including Bacteroides spp., Fusobacterium spp., Porphyromonas spp., Prevotella spp., and Veillonella parvula (8).
Our data revealed that organisms other than staphylococci, specifically M. catarrhalis, Escherichia coli, and Klebsiella pneumoniae, that possess FabI as their sole enoyl-ACP reductase (10) were nonsusceptible to AFN-1252. Staphylococci, E. coli, M. catarrhalis, and Haemophilus influenzae have been shown previously to possess FabI and to lack an alternative enzyme or rescue pathway (1). We speculate that M. catarrhalis, E. coli, and K. pneumoniae are not susceptible to AFN-1252, despite possessing FabI as their sole enoyl-ACP reductase, because these gram-negative organisms may possess an efflux mechanism for or present a permeability barrier to AFN-1252. AFN-1252 may be a substrate for the acrAB efflux pump of E. coli, as the AFN-1252 MIC for an acrAB-deficient mutant (AG100a ΔacrAB) has been demonstrated previously to be 0.016 μg/ml while the MIC for the parental strain (AG100) is >32 μg/ml (8). The FabI active sites of these gram-negative bacteria have structural differences from the S. aureus active site used to direct the iterative structure-guided development of AFN-1252 (Affinium Pharmaceuticals, Inc., unpublished data). Alternatively, FabI may be overexpressed in these species, as the overexpression of FabI in S. aureus has been reported to reduce the activity of triclosan, an agent whose mechanism of action also involves interaction with FabI (11).
In conclusion, escalating rates of resistance may limit the clinical utility of some currently marketed antibacterial agents and underlie the search for new classes of agents with novel mechanisms of action. AFN-1252 is a promising new agent with the potential to treat patients with staphylococcal infections known or suspected to be resistant to conventional antistaphylococcal therapies in both hospital and outpatient settings. These data support the continued development of AFN-1252 for the treatment of patients with resistant staphylococcal infections.
Acknowledgments
We thank the investigators and laboratory site staff at each medical center that participated in the CANWARD 2007 study. The medical centers (investigators) were as follows: Royal University Hospital, Saskatoon, SK (J. Blondeau); Children's Hospital of Eastern Ontario, Ottawa, ON (F. Chan); Queen Elizabeth II Health Sciences Centre and Dartmouth General/Izaak Walton Killam Health Centre, Halifax, NS (R. Davidson); Health Sciences Centre, Winnipeg, MB (D. Hoban, G. Zhanel); London Health Sciences Centre, London, ON (Z. Hussain); Hôpital Maisonneuve-Rosemont, Montreal, QC (M. Laverdière); St. Joseph's Hospital, Hamilton, ON (C. Lee); Montreal General Hospital/Royal Victoria Hospital, Montreal, QC (V. Loo); Mount Sinai Hospital, Toronto, ON (S. Poutanen); University of Alberta Hospitals, Edmonton, AB (R. Rennie); and Vancouver Hospital, Vancouver, BC (D. Roscoe).
The CANWARD 2007 study was supported in part by Affinium Pharmaceuticals, Inc., Toronto, ON, Canada. CANWARD 2007 data can be viewed at www.can-r.ca.
Footnotes
Published ahead of print on 1 June 2009.
REFERENCES
- 1.Campbell, J. W., and J. E. Cronan, Jr. 2001. Bacterial fatty acid biosynthesis: targets for antibacterial drug discovery. Annu. Rev. Microbiol. 55:305-332. [DOI] [PubMed] [Google Scholar]
- 2.Clinical and Laboratory Standards Institute. 2007. Performance standards for antimicrobial susceptibility testing; eighteenth informational supplement, M100-S17, vol. 27, no. 1. Clinical and Laboratory Standards Institute, Wayne, PA.
- 3.Clinical and Laboratory Standards Institute. 2006. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; M7-A7, approved standard, 7th ed. Clinical and Laboratory Standards Institute, Wayne, PA.
- 4.Reference deleted.
- 5.Reference deleted.
- 6.Heath, R. J., and C. O. Rock. 2000. A triclosan-resistant bacterial enzyme. Nature 406:145. [DOI] [PubMed] [Google Scholar]
- 7.Heath, R. J., S. W. White, and C. O. Rock. 2002. Inhibitors of fatty acid synthesis as antimicrobial chemotherapeutics. Appl. Microbiol. Biotechnol. 58:695-703. [DOI] [PubMed] [Google Scholar]
- 8.Kaplan, N., B. Hafkin, R. Schaadt, D. Sweeney, D. Shinabarger, and G. Zurenko. 2008. Specific spectrum activity of AFN-1252 against aerobic and anaerobic bacterial pathogens, abstr. F1-341. Abstr. 48th Intersci. Conf. Antimicrob. Agents Chemother.
- 9.Karlowsky, J. A., N. M. Laing, T. Baudry, N. Kaplan, D. Vaughan, D. J. Hoban, and G. G. Zhanel. 2007. In vitro activity of API-1252, a novel FabI inhibitor, against clinical isolates of Staphylococcus aureus and Staphylococcus epidermidis. Antimicrob. Agents Chemother. 51:1580-1581. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Payne, D. J., W. H. Miller, V. Berry, J. Brosky, W. J. Burgess, E. Chan, W. E. Wolfe, Jr., A. P. Fosberry, R. Greenwood, M. S. Head, D. A. Heerding, C. A. Janson, D. D. Jaworski, P. M. Keller, P. J. Manley, T. D. Moore, K. A. Newlander, S. Pearson, B. J. Polizzi, X. Qiu, S. F. Rittenhouse, C. Slater-Radosti, K. L. Salyers, M. A. Seefeld, M. G. Smyth, D. T. Takata, I. N. Uzinskas, K. Vaidya, N. G. Wallis, S. B. Winram, C. C. K. Yuan, and W. F. Huffman. 2002. Discovery of a novel and potent class of FabI-directed antibacterial agents. Antimicrob. Agents Chemother. 46:3118-3124. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Slater-Radosti, C., G. Van Aller, R. Greenwood, R. Nicholas, P. M. Keller, W. E. DeWolf, Jr., F. Fan, D. J. Payne, and D. D. Jaworski. 2001. Biochemical and genetic characterization of the action of triclosan on Staphylococcus aureus. J. Antimicrob. Chemother. 48:1-6. [DOI] [PubMed] [Google Scholar]
- 12.Weiss, W. J., B. Hafkin, N. Kaplan, M. Pulse, and P. Nguyen. 2008. Efficacy of AFN-1252 and vancomycin in the mouse subcutaneous abscess model with a methicillin-resistant S. aureus, abstr. F1-329. Abstr. 48th Intersci. Conf. Antimicrob. Agents Chemother.