Antibacterial activity of BMS-180680, a new catechol-containing monobactam

Abstract

The in vitro activities of a new catechol-containing monobactam, BMS-180680 (SQ 84,100), were compared to those of aztreonam, ceftazidime, imipenem, piperacillin-tazobactam, ciprofloxacin, amikacin, and trimethoprim-sulfamethoxazole. BMS-180680 was often the most active compound against many species of the family Enterobacteriaceae, with MICs at which 90% of the isolates were inhibited (MIC90s) of < or = 0.5 microg/ml for Escherichia coli, Klebsiella spp., Citrobacter diversus, Enterobacter aerogenes, Serratia marcescens, Proteus spp., and Providencia spp. BMS-180680 had moderate activities (MIC90s of 2 to 8 microg/ml) against Citrobacter freundii, Morganella morganii, Shigella spp., and non-E. aerogenes Enterobacter spp. BMS-180680 was the only antibiotic evaluated that was active against >90% of the Pseudomonas aeruginosa (MIC90, 0.25 microg/ml), Burkholderia cepacia, and Stenotrophomonas maltophilia (MIC90s, 1 microg/ml) strains tested. BMS-180680 was inactive against most strains of Pseudomonas fluorescens, Pseudomonas stutzeri, Pseudomonas diminuta, and Burkholderia pickettii. BMS-180680 was moderately active (MIC90s of 4 to 8 microg/ml) against Alcaligenes spp. and Acinetobacter lwoffii and less active (MIC90, 16 microg/ml) against Acinetobacter calcoaceticus-Acinetobacter baumanii complex. BMS-180680 lacked activity against gram-positive bacteria and anaerobic bacteria. Both tonB and cir fiu double mutants of E. coli had greatly decreased susceptibility to BMS-180680. Of the TEM, PSE, and chromosomal-encoded beta-lactamases tested, only the K1 enzyme hydrolyzed BMS-180680 to any measurable extent. Like aztreonam, BMS-180680 bound preferentially to penicillin-binding protein 3. The MICs of BMS-180680 were not influenced by the presence of hematin or 5% sheep blood in the test medium or with incubation in an atmosphere containing 5% CO2. BMS-180680 MICs obtained under strict anaerobic conditions were significantly higher than those obtained in ambient air.

Antibacterial and β‐Lactamase Inhibitory Activity of Monocyclic β‐Lactams

“…The researchers from Bristol Myers Squibb described the in vitro activity of monobactam derivative 164 , containing a catechol analogue, 6,7‐dihydroxyquinoxaline, directly attached to the oxime side chain at position 3 of the β‐lactam ring (BMS‐180680 164 ; Fig. ) . This structural feature enabled the compound to utilize the Cir and Fiu iron‐regulated outer membrane receptor proteins and the TonB‐dependent iron transport system for enhanced uptake across the bacterial outer membrane.…”

Siderophore conjugates

“…Catecholate and hydroxamate conjugates of oxamazin‐type monocyclic β‐lactams have been investigated but were found to promote growth through their siderophore activity, rather than inhibit it through their antibiotic activity 56,57,66 . Catecholate monobactams were explored at Bristol‐Myers Squibb, giving rise to BMS‐180680, which showed a spectrum like aztreonam, with some enhancement of activity against P. aeruginosa and S. maltophilia 67 . Like other catecholate conjugates, BMS‐180680 showed elevated MICs for E. coli strains with defects in TonB and Cir/Fiu double mutations 67 .…”

“…Catecholate monobactams were explored at Bristol‐Myers Squibb, giving rise to BMS‐180680, which showed a spectrum like aztreonam, with some enhancement of activity against P. aeruginosa and S. maltophilia 67 . Like other catecholate conjugates, BMS‐180680 showed elevated MICs for E. coli strains with defects in TonB and Cir/Fiu double mutations 67 . Siderophore monobactams in which a hydroxypyridone moiety is carried on the oxyaminoacylamino side were pursued by the Takeda and Synphar companies, giving rise to PTX 2416 ( 43 ) 68,69 .…”

Electrochemical oxidation of substituted catechols in the presence of pyrazol-5-ones: characterization of products and reaction mechanism

“…Moreover, most of compounds incorporating catechol moiety exhibit antioxidant, 1 anticarcinogenic, 2,3 antifungous, 4 and antibacterial activities 5,6 or are used as HIV integrase inhibitors. 7e9 For example, dopamine is a neurotransmitter in the central nervous system of human and other vertebrate animals, 10 whereas, dicaffeoyltartaric acid 7 and dicaffeoylquinic acid 7,8 …”