Synthesis and SAR of novel parenteral anti-pseudomonal cephalosporins: Discovery of FR264205

In Vivo Comparison of CXA-101 (FR264205) with and without Tazobactam versus Piperacillin-Tazobactam Using Human Simulated Exposures against Phenotypically Diverse Gram-Negative Organisms

“…The piperacillin-tazobactam regimens demonstrated anywhere between a 0.5-log-unit increase and a Ͻ1-log-unit decrease in bacterial density. While the resistance mechanism(s) in the abovementioned pseudomonads have not been characterized, it is postulated that the enhanced activity of the CXA-101 regimens may in part be due to the compound's improved stability against AmpC ␤-lactamases and/or increased affinity for PBP3 (23). This increased affinity for PBP3 allows CXA-101 to be less affected and, in most cases, unaffected by porin deficiencies or efflux mechanisms (23).…”

“…It has recently been shown to have in vitro activity against multidrug-resistant Gram-negative organisms, especially when ␤-lactamase inhibitors were added to this agent (11,5). It demonstrates increased stability against AmpC ␤-lactamase-producing organisms and, through increased binding to penicillin-binding protein 3 (PBP3), has been shown to have activity against organisms with porin deficiencies and efflux mechanisms (23). Here, we compared the in vivo bactericidal efficacy of CXA-101 with or without tazobactam to that of piperacillintazobactam through the use of human simulated exposures in an immunocompetent murine thigh infection model with multidrugresistant P. aeruginosa and ESBL-positive and -negative E. coli and K. pneumoniae.…”

Targeting Antibiotic Resistance

“…Indeed, allosteric interactions are required to trigger a conformational change that opens the active site. Following these findings, three so‐called “fifth‐generation” cephalosporins, namely ceftaroline,144 ceftobiprole,145 and ceftolozane,146 were developed by following the currently known SAR (Figure 30), and these show activity against MRSA. …”

“…It maintains the aminothiadiazole ring and oxime functional groups of ceftaroline and ceftobiprole, which confer enhanced activity against Gram‐negative bacilli and stability against β‐lactamases, respectively 151. Additionally the appended dimethylacetic acid moiety provides improved antipseudomonal activity 146, 151. On the eastern side, a highly substituted pyrazole ring provides the steric bulk necessary to reduce hydrolysis by β‐lactamases 151.…”

“…On the eastern side, a highly substituted pyrazole ring provides the steric bulk necessary to reduce hydrolysis by β‐lactamases 151. The SAR of the substitution pattern of the pyrazole ring was studied in detail, and a 5‐amino‐1‐methyl‐1 H ‐pyrazol‐2‐ium moiety was found to confer the highest antipseudomonal activity 146. Additionally, the basicity of the substituent at the 3‐position of the cephalosporin nucleus could be correlated with improved outer membrane permeability.…”