Synthesis of Carbapenems Containing Peptidoglycan Mimetics and Inhibition of the Cross‐Linking Activity of a Transpeptidase of l,d Specificity

Abstract

The carbapenem class of β‐lactams has been optimized against Gram‐negative bacteria producing extended‐spectrum β‐lactamases by introducing substituents at position C2. Carbapenems are currently investigated for the treatment of tuberculosis as these drugs are potent covalent inhibitors of l,d‐transpeptidases involved in mycobacterial cell wall assembly. The optimization of carbapenems for inactivation of these unusual targets is sought herein by exploiting the nucleophilicity of the C8 hydroxyl group to introduce chemical diversity. As β‐lactams are structure analogs of peptidoglycan precursors, the substituents were chosen to increase similarity between the drug and the substrate. Fourteen peptido‐carbapenems were efficiently synthesized. They were more effective than the reference drug, meropenem, owing to the positive impact of a phenethylthio substituent introduced at position C2 but the peptidomimetics added at position C8 did not further improve the activity. Thus, position C8 can be modified to modulate the pharmacokinetic properties of highly efficient carbapenems.

Mechanistic Insights into the Activities of Major Families of Enzymes in Bacterial Peptidoglycan Assembly and Breakdown

“…Unfortunately, the success of such "peptidoglycan mimetics" has been mixed. [108][109][110][111][112] For instance, the introduction of two extended arms to the cephalosporin core with peptide motifs that mimic the acyl donor and the acyl acceptor, respectively, improved the compound's specificity: it inhibited the TP activity of E. coli PBP1b selectively in vitro but showed no interaction or inhibition against E. coli PBP5 (a carboxypeptidase, CP). [111] In another work, Josephine et al demonstrated that the addition of side chain extensions onto β-lactams unexpectedly improved the inhibition of LMW PBPs, but not the bPBPs in vitro.…”

“…Given that β‐lactams mimic the d ‐Ala (IV) ‐ d ‐Ala (V) terminus of the acyl acceptor in the transpeptidation reaction, efforts have been made to rationally modify the β‐lactam core with side chain extensions that resemble the canonical stem peptide or branch peptide. Unfortunately, the success of such “peptidoglycan mimetics” has been mixed [108–112] . For instance, the introduction of two extended arms to the cephalosporin core with peptide motifs that mimic the acyl donor and the acyl acceptor, respectively, improved the compound's specificity: it inhibited the TP activity of E. coli PBP1b selectively in vitro but showed no interaction or inhibition against E. coli PBP5 (a carboxypeptidase, CP) [111] .…”

“…demonstrated that the addition of side chain extensions onto β‐lactams unexpectedly improved the inhibition of LMW PBPs, but not the bPBPs in vitro [108] . Similarly, the inclusion of stem peptide or branch peptide mimics to a carbapenem scaffold did not improve its inhibition of E. faecium LDT (Ldt FM ) [110] . While these results could potentially be attributed to the different substrate recognition and specificity of different PBPs, the fact that these compounds showed limited activity against PBPs in biochemical assays dampens the excitement of evaluating their antibacterial potential against bacterial cells.…”

Structure–Activity Relationship of Penem Antibiotic Side Chains Used against Mycobacteria Reveals Highly Active Compounds

“…Carbapenems have been heavily explored with multiple drugs on the market, while penems are only represented commercially by faropenem. Meropenem, a member of the carbapenem subclass, in combination with clavulanate, a β-lactamase inhibitor, has shown unmistakable bactericidal activity in the sputum of TB patients and has been used effectively in the clinic for treating MDR TB infections. − These results have spurred interest in developing new carbapenems against Mtb . , The recent development of atypical carbapenems has shown promising progress against Mtb and Mab . Additionally, faropenem and the newly developed penem T405 have displayed potent activity against Mtb and Mab . , While carbapenems have been the main focus in β-lactam development against TB, penems remain relatively unexplored.…”

“…12−15 These results have spurred interest in developing new carbapenems against Mtb. 16,17 The recent development of atypical carbapenems has shown promising progress against Mtb and Mab. 18 activity against Mtb and Mab.…”