Novel cephalosporins. Modification of the carbon-4 carboxyl group

Jen, Timothy; Dienel, B.; Frazee, James S.; Weisbach, Jerry A.

doi:10.1021/jm00281a020

Cited by 16 publications

(1 citation statement)

References 9 publications

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“…Further suggesting the likelihood of non-canonical targets, the NR-active cephalosporins bear an ester or an oxadiazole (an ester isostere) at the C2 position of the cephalosporin core, rather than the free carboxylic acid characteristic of inhibitory cephalosporins (Chauvette and Flynn, 1966;Jen et al, 1972). The importance of the free carboxylic acid is highlighted in the crystal structure of the acyl-enzyme tetrahedral intermediate between PBP2x from Streptococcus pneumoniae and cefuroxime, which showed tight hydrogen bonding between Thr550 in the active site and the carboxylic acid of cefuroxime (Gordon et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Activity-Based Protein Profiling Reveals That Cephalosporins Selectively Active on Non-replicating Mycobacterium tuberculosis Bind Multiple Protein Families and Spare Peptidoglycan Transpeptidases

et al. 2020

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As β-lactams are reconsidered for the treatment of tuberculosis (TB), their targets are assumed to be peptidoglycan transpeptidases, as verified by adduct formation and kinetic inhibition of Mycobacterium tuberculosis (Mtb) transpeptidases by carbapenems active against replicating Mtb. Here, we investigated the targets of recently described cephalosporins that are selectively active against non-replicating (NR) Mtb. NR-active cephalosporins failed to inhibit recombinant Mtb transpeptidases. Accordingly, we used alkyne analogs of NR-active cephalosporins to pull down potential targets through unbiased activity-based protein profiling and identified over 30 protein binders. None was a transpeptidase. Several of the target candidates are plausibly related to Mtb's survival in an NR state. However, biochemical tests and studies of loss of function mutants did not identify a unique target that accounts for the bactericidal activity of these beta-lactams against NR Mtb. Instead, NR-active cephalosporins appear to kill Mtb by collective action on multiple targets. These results highlight the ability of these β-lactams to target diverse classes of proteins.

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Section: Introductionmentioning

confidence: 99%