Assessment of carbapenems in a mouse model of Mycobacterium tuberculosis infection

Abstract

We present further study of a subset of carbapenems, arising from a previously reported machine learning approach, with regard to their mouse pharmacokinetic profiling and subsequent study in a mouse model of sub-acute Mycobacterium tuberculosis infection. Pharmacokinetic metrics for such small molecules were compared to those for meropenem and biapenem, resulting in the selection of two carbapenems to be assessed for their ability to reduce M. tuberculosis bacterial loads in the lungs of infected mice. The original syntheses of these two carbapenems were optimized to provide multigram quantities of each compound. One of the two experimental carbapenems, JSF-2204, exhibited efficacy equivalent to that of meropenem, while both were inferior to rifampin. The lessons learned in this study point toward the need to further enhance the pharmacokinetic profiles of experimental carbapenems to positively impact in vivo efficacy performance.

T405, a New Penem, Exhibits In Vivo Efficacy against M. abscessus and Synergy with β-Lactams Imipenem and Cefditoren

“…We leveraged precedents on M. tuberculosis l,d -transpeptidases and carbapenems/penems guided by crystal structures ( 52 , 53 , 57 – 62 ) to develop improved inhibitors of M. tuberculosis l,d -transpeptidases with the hypothesis that unique penems may exhibit improved potency against this microbe. Similar attempts at developing unique and potent inhibitors of l,d -transpeptidases using the β-lactam core have been reported independently ( 63 – 65 ). While a select few new penems exhibited desirable MICs against M. tuberculosis , we were gratified to find that one of these penems, T405, had MICs lower than those of imipenem and faropenem against a collection of Mab isolates ( 33 ).…”

Tuberculosis Drug Discovery: Challenges and New Horizons

“…Both types are uniquely and covalently inhibited by carbapenems, broad-spectrum antibacterial agents from the β-lactam class; two such drugs, imipenem ( 12 ) and meropenem ( 13 ), are listed in Table as Group C medicines for the treatment of MDR-TB. However, the need to give those drugs every 8 or 12 h by slow infusion (optimally with a β-lactamase inhibitor to reduce metabolism by the Mtb β-lactamase BlaC) has limited their clinical use, stimulating further research to find more suitable analogues . Several cocrystal structures of carbapenem l , d -transpeptidases with inhibitors have afforded a better understanding of mechanistic and physical details relevant to this task. , …”

“…Mouse efficacy studies of known carbapenems have often been limited by PK issues, particularly their short half-lives [0.29 h for 80 , 0.46 h for meropenem ( 13 )]. ,, As part of the above investigations, a small set of additional analogues was prepared and JSF-2204 ( 82 ) (Figure ) was identified as the best lead. This molecule showed improved potency against Mtb H37Rv (MIC 90 0.90 vs 10 μM for 13 ) and, unlike 80 , gave a stable adduct with l , d -transpeptidase-2 based on the entire molecule (confirmed by a cocrystal structure) .…”

“…This molecule showed improved potency against Mtb H37Rv (MIC 90 0.90 vs 10 μM for 13 ) and, unlike 80 , gave a stable adduct with l , d -transpeptidase-2 based on the entire molecule (confirmed by a cocrystal structure) . Although the half-life of 82 in mice (0.24 h) remained an issue, this compound was further tested alongside meropenem ( 13 ) in the acute Mtb infection BALB/c mouse model . Both drugs were administered subcutaneously at 400 mg/kg (twice daily for 3 weeks, together with the β-lactamase inhibitor sodium clavulanate at 75 mg/kg), resulting in equivalent but moderate efficacy (<2.0 log 10 CFU reduction in bacterial lung burden, compared to the untreated control).…”

“…However, the need to give those drugs every 8 or 12 h by slow infusion (optimally with a β-lactamase inhibitor to reduce metabolism by the Mtb βlactamase BlaC) has limited their clinical use, stimulating further research to find more suitable analogues. 211 Several cocrystal structures of carbapenem L,D-transpeptidases with inhibitors have afforded a better understanding of mechanistic and physical details relevant to this task. 212,213 Biapenem (80) (Figure 9) is a newer, more stable carbapenem (approved in Japan, China, and India) that has recently been evaluated for use against DS and RIF-resistant Mtb.…”