Atypically Modified Carbapenem Antibiotics Display Improved Antimycobacterial Activity in the Absence of β-Lactamase Inhibitors (original) (raw)
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2014
The genome of Mycobacterium tuberculosis contains a gene, blaC, which encodes a highly active β-lactamase (BlaC). We have previously shown that BlaC has an extremely broad spectrum of activity against penicillins and cephalosporins but weak activity against newer carbapenems. We have shown that carbapenems such as meropenem, doripenem, and ertapenem react with the enzyme to form enzyme−drug covalent complexes that are hydrolyzed extremely slowly. In the current study, we have determined apparent K m and k cat values of 0.8 μM and 0.03 min −1 , respectively, for tebipenem, a novel carbapenem whose prodrug form, the pivalyl ester, is orally available. Tebipenem exhibits slow tightbinding inhibition at low micromolar concentrations versus the chromogenic substrate nitrocefin. FT-ICR mass spectrometry demonstrated that the tebipenem acyl−enzyme complex remains stable for greater than 90 min and exists as mixture of the covalently bound drug and the bound retro-aldol cleavage product. We have also determined the high-resolution crystal structures of the BlaC−tebipenem covalent acylated adduct (1.9 Å) with wild-type BlaC and the BlaC−tebipenem Michaelis− Menten complex (1.75 Å) with the K73A BlaC variant. These structures are compared to each other and to other carbapenem− BlaC structures.
Biochemistry, 2014
The genome of Mycobacterium tuberculosis contains a gene, blaC, which encodes a highly active β-lactamase (BlaC). We have previously shown that BlaC has an extremely broad spectrum of activity against penicillins and cephalosporins but weak activity against newer carbapenems. We have shown that carbapenems such as meropenem, doripenem, and ertapenem react with the enzyme to form enzyme−drug covalent complexes that are hydrolyzed extremely slowly. In the current study, we have determined apparent K m and k cat values of 0.8 μM and 0.03 min −1 , respectively, for tebipenem, a novel carbapenem whose prodrug form, the pivalyl ester, is orally available. Tebipenem exhibits slow tightbinding inhibition at low micromolar concentrations versus the chromogenic substrate nitrocefin. FT-ICR mass spectrometry demonstrated that the tebipenem acyl−enzyme complex remains stable for greater than 90 min and exists as mixture of the covalently bound drug and the bound retro-aldol cleavage product. We have also determined the high-resolution crystal structures of the BlaC−tebipenem covalent acylated adduct (1.9 Å) with wild-type BlaC and the BlaC−tebipenem Michaelis− Menten complex (1.75 Å) with the K73A BlaC variant. These structures are compared to each other and to other carbapenem− BlaC structures.
BMC biochemistry, 2017
The carbapenem subclass of β-lactams is among the most potent antibiotics available today. Emerging evidence shows that, unlike other subclasses of β-lactams, carbapenems bind to and inhibit non-classical transpeptidases (L,D-transpeptidases) that generate 3 → 3 linkages in bacterial peptidoglycan. The carbapenems biapenem and tebipenem exhibit therapeutically valuable potencies against Mycobacterium tuberculosis (Mtb). Here, we report the X-ray crystal structures of Mtb L,D-transpeptidase-2 (LdtMt2) complexed with biapenem or tebipenem. Despite significant variations in carbapenem sulfur side chains, biapenem and tebipenem ultimately form an identical adduct that docks to the outer cavity of LdtMt2. We propose that this common adduct is an enzyme catalyzed decomposition of the carbapenem adduct by a mechanism similar to S-conjugate elimination by β-lyases. The results presented here demonstrate biapenem and tebipenem bind to the outer cavity of LdtMt2, covalently inactivate the enz...
Frontiers in Pharmacology, 2023
KEYWORDS anti-TB drug development, drug development strategies against tuberculosis, natural product-based drug discovery, bioinformatics tools, medicinal chemistry and drug synthesis Editorial on the Research Topic Drug-ability strategies for potential antimycobacterial candidate: opportunities and challenges Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is an infectious killer with a higher prevalence rate (10.6 million) and mortality rate (1.6 million) across the globe as per the WHO-Global Tuberculosis Report-2022 (Swain et al., 2022; WHO, 2022). After continuous scientific research efforts and socio-political awareness campaigns, we are unable to control emerging drug-resistant strains of Mtb. In the last two decades, only three anti-TB drugs (bedaquiline, delanamid, and pretomanid) have been approved by the FDA, which creates havoc in anti-TB therapy as well in primary healthcare system. In addition, long-term anti-TB therapy has shown several common (gastrointestinal intolerance, headache, diarrhoea, etc.) to severe (hepato-and neurotoxic) side effects. Therefore, several ingenious attempts have been made to improve early diagnosis and locate or design potential anti-TB candidates (Acharya et al., 2020; Swain et al., 2020; Dong et al., 2022; Swain and Hussain, 2022). Four articles have been published in the first edition of the Research Topic. As the ultimate goal is to control Mtb, all have used different modalities and expertise to accelerate anti-TB drug development modules, which are introduced here. Tanner et al. developed three newer versions of the existing anticoccidial drug decoquinate (DQ) through an ingenious medicinal chemistry protocol. DQ is a potent quinolone nucleus-bearing antiparasite medication used to prevent coccidian infections in poultry feed for over 50 years and reported as having no activity against Mtb, with poor druglikeness and low water solubility profiles. The proposed derivatives (RMB041, RMB043, and RMB073) bearing an alkyl group at N-1 with amide groups at C-3 substitutions exhibited potential anti-TB activity with 90% minimum inhibitory concentrations (MIC 90), 1.61, 4.18, and 1.88 µM against the Mtb H37Rv strain. Further, DQ-derivatives showed higher
Tuberculosis
Mycobacterium tuberculosis (Mtb) Tuberculosis (TB) Methionine aminopeptidase (MetAP) Clioquinol (CQ) 7-bromo-5-chloroquinolin-8-ol (CLBQ14) s u m m a r y Mycobacterium tuberculosis, the causative agent of tuberculosis claims about five thousand lives daily world-wide, while one-third of the world is infected with dormant tuberculosis. The increased emergence of multi-and extensively drug-resistant strains of M. tuberculosis (Mtb) has heightened the need for novel antimycobacterial agents. Here, we report the discovery of 7-bromo-5-chloroquinolin-8-ol (CLBQ14)-a congener of clioquinol (CQ) as a potent and selective inhibitor of two methionine aminopeptidases (MetAP) from M. tuberculosis: MtMetAP1a and MtMetAP1c. MetAP is a metalloprotease that removes the N-terminal methionine during protein synthesis. N-terminal methionine excision (NME) is a universally conserved process required for the post-translational modification of a significant part of the proteome. The essential role of MetAP in microbes makes it a promising target for the development of new therapeutics. Using a target-based approach in a high-throughput screen, we identified CLBQ14 as a novel MtMetAP inhibitor with higher specificity for both MtMetAP1s relative to their human counterparts. We also found that CLBQ14 is potent against replicating and aged non-growing Mtb at low micro molar concentrations. Furthermore, we observed that the antimycobacterial activity of this pharmacophore correlates well with in vitro enzymatic inhibitory activity. Together, these results revealed a new mode of action of clioquinol and its congeners and validated the therapeutic potential of this pharmacophore for TB chemotherapy.