bal-30072 and Gram-Negative-Bacterial-Infections

Topics: Animals; Anti-Bacterial Agents; Drug Discovery; Drug Resistance, Multiple, Bacterial; Escherichia coli; Escherichia coli Infections; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Klebsiella Infections; Klebsiella pneumoniae; Male; Mice; Microbial Sensitivity Tests; Monobactams; Pyridones; Rats, Sprague-Dawley; Structure-Activity Relationship; Thiazoles

A series of monobactam derivatives were prepared and evaluated for their antibacterial activities against susceptible and resistant Gram-negative strains, taking Aztreonam and BAL30072 as the leads. Six conjugates (12a-f) bearing PIH-like siderophore moieties were created to enhance the bactericidal activities against Gram-negative bacteria based on Trojan Horse strategy, and all of them displayed potencies against susceptible Gram-negative strains with MIC ≤ 8 μg/mL. SAR revealed that the polar substituents on the oxime side chain were beneficial for activities against resistant Gram-negative bacteria. Compounds 19c and 33a-b exhibited the promising potencies against ESBLs-producing E. coli and Klebsiella pneumoniae with MICs ranging from 2 μg/mL to 8 μg/mL. These results offered powerful information for further strategic optimization in search of the antibacterial candidates against MDR Gram-negative bacteria.

Topics: Anti-Bacterial Agents; Aztreonam; Drug Design; Escherichia coli; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Klebsiella pneumoniae; Microbial Sensitivity Tests; Models, Molecular; Monobactams; Structure-Activity Relationship; Thiazoles

The in vitro activity of BAL30072 was assessed against clinical isolates from NYC hospitals, including isolates from a citywide surveillance study and a collection of isolates with well-characterised resistance mechanisms. BAL30072 was the most active β-lactam against Pseudomonas aeruginosa (MIC50/90, 0.25/1 μg/mL), Acinetobacter baumannii (MIC50/90, 4/>64 μg/mL) and KPC-possessing Klebsiella pneumoniae (MIC50/90, 4/>64 μg/mL). Combining BAL30072 with meropenem resulted in a ≥ 4-fold decrease in the BAL30072 MIC90 both for A. baumannii and K. pneumoniae. For isolates with a BAL30072 MIC>4 μg/mL, addition of a sub-MIC concentration of colistin resulted in a four-fold decrease in the BAL30072 MIC in 44% of P. aeruginosa, 82% of A. baumannii and 23% of K. pneumoniae. Using sub-MIC concentrations, BAL30072 plus colistin was bactericidal against 4 of 11 isolates in time-kill studies. BAL30072 MICs were frequently lower for P. aeruginosa and K. pneumoniae when tested using Mueller-Hinton agar versus Iso-Sensitest agar or Mueller-Hinton broth. Against the well-characterised isolates, reduced susceptibility to BAL30072 correlated with mexA and mexX expression (P. aeruginosa), adeB expression (A. baumannii) and presence of SHV-type ESBLs (A. baumannii and K. pneumoniae). BAL30072 shows promising activity against contemporary Gram-negatives, including MDR P. aeruginosa, A. baumannii and K. pneumoniae. Enhanced activity was often present when BAL30072 was combined with meropenem or colistin. BAL30072 MICs were influenced by the testing method, particularly for P. aeruginosa and K. pneumoniae. Further in vivo studies are warranted to determine the potential clinical utility of BAL30072 alone and combined with other agents.

Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Gram-Negative Bacterial Infections; Humans; Klebsiella pneumoniae; Microbial Sensitivity Tests; Monobactams; New York City; Pseudomonas aeruginosa; Thiazoles

The problem of antimicrobial resistance is exemplified by multidrug-resistant (MDR) isolates of Gram-negative species. Of particular concern are expanded-spectrum cephalosporin-resistant isolates of Enterobacteriaceae, epidemic lineages of Acinetobacter baumannii producing OXA-type carbapenemases, and MDR Pseudomonas aeruginosa. In this study, the in vitro activity of the novel monosulfactam BAL30072 was investigated both alone and in combination with meropenem against a diverse collection of commonly encountered Gram-negative pathogens. Thirty-one isolates were studied, including type strains and clinical isolates with defined mechanisms conferring resistance to various antimicrobial agents including to carbapenems, colistin and tigecycline. BAL30072 minimum inhibitory concentrations (MICs) were determined in the presence and absence of meropenem (1:1, w/w) by agar dilution. Potential synergy or antagonism between BAL30072 and meropenem was investigated using standard chequerboard assays. Versus MDR A. baumannii strains producing class D oxacillinases, BAL30072 MICs were all ≤4 mg/L with the exception of the isolate belonging to the UK 'Burn' lineage. BAL30072 exhibited MIC values of 0.5 mg/L to >64 mg/L towards the five P. aeruginosa strains. Against three meropenem-susceptible Escherichia coli, including the CTX-M-15 extended-spectrum β-lactamase-producer, BAL30072 exhibited MICs of 0.25-2 mg/L; higher MICs were recorded against some of the Enterobacteriaceae isolates tested. The in vitro data suggest that BAL30072 has a potential role in the treatment of infections due to Gram-negative pathogens, including those with important resistances to other agents. In addition, BAL30072 shows powerful synergistic activity in combination with meropenem, potentially expanding its coverage for the treatment of infections caused by problematic species.

Topics: Anti-Bacterial Agents; Drug Synergism; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Meropenem; Microbial Sensitivity Tests; Monobactams; Thiazoles; Thienamycins

Novel siderophore-linked monobactams with in vitro and in vivo anti-microbial activity against MDR Gram-negative pathogens are described.

Topics: Animals; Binding Sites; Blood Proteins; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Mice; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Monobactams; Rats; Structure-Activity Relationship