N-Thio-β-lactams targeting L,D-transpeptidase-2, with activity against drug-resistant strains of Mycobacterium tuberculosis

Martelli, Giulia; Pessatti, Tomás Bohn; Steiner, Eva Maria; Cirillo, Martina; Caso, Carolina; Bisognin, Francesco; Landreh, Michael; Monte, Paola Dal; Giacomini, Daria; Schnell, R.

doi:10.1016/j.chembiol.2021.03.008

Cited by 7 publications

(8 citation statements)

References 66 publications

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“…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 ).…”

Section: Discussionmentioning

confidence: 60%

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

Rimal

Batchelder

Story-Roller

et al. 2022

Antimicrob Agents Chemother

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Section: Discussionmentioning

confidence: 60%

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

Rimal

Batchelder

Story-Roller

et al. 2022

Antimicrob Agents Chemother

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“…This is an especially useful approach as multidrug resistant microbes can persist in the environment and do not readily reverse even upon discontinuation of the treatment [ 104 ]. For example, N-thiol substituted monocyclic β-lactams covalently inhibits abundant L-D transpeptidase 2 which performs 3,3-diaminopimelic acid crosslinks in peptidoglycan of Mycobacterium tuberculosis thereby being effective against dormant and multidrug resistant isolates [ 105 ]. It has also been observed that the frequency of horizontal plasmid transfer increases in the presence of subinhibitory concentrations of antibiotics [ 106 ].…”

Section: Innovative Strategies To Overcome Antimicrobial Resistancementioning

confidence: 99%

Innovative Strategies to Overcome Antimicrobial Resistance and Tolerance

et al. 2022

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Antimicrobial resistance and tolerance are natural phenomena that arose due to evolutionary adaptation of microorganisms against various xenobiotic agents. These adaptation mechanisms make the current treatment options challenging as it is increasingly difficult to treat a broad range of infections, associated biofilm formation, intracellular and host adapted microbes, as well as persister cells and microbes in protected niches. Therefore, novel strategies are needed to identify the most promising drug targets to overcome the existing hurdles in the treatment of infectious diseases. Furthermore, discovery of novel drug candidates is also much needed, as few novel antimicrobial drugs have been introduced in the last two decades. In this review, we focus on the strategies that may help in the development of innovative small molecules which can interfere with microbial resistance mechanisms. We also highlight the recent advances in optimization of growth media which mimic host conditions and genome scale molecular analyses of microbial response against antimicrobial agents. Furthermore, we discuss the identification of antibiofilm molecules and their mechanisms of action in the light of the distinct physiology and metabolism of biofilm cells. This review thus provides the most recent advances in host mimicking growth media for effective drug discovery and development of antimicrobial and antibiofilm agents.

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“…It was demonstrated that the inhibition of transpeptidase Ldt Mt2 of Mycobacterium tuberculosis occurs on transfer of the thio residue from the nitrogen atom of the β-lactam to the cysteine residue of the active site of the transpeptidase, thus forming a covalent disulfide adduct with the protein, as revealed by mass spectrometry (Figure B) …”

Section: Introductionmentioning

confidence: 99%

N-Sulfenylation of β-Lactams: Radical Reaction of N-Bromo-azetidinones by TEMPO Catalysis

Giraldi,

Giunchino,

Casacchia

et al. 2023

J. Org. Chem.

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Azetidinones with a sulfenyl group on the β-lactam nitrogen atom show interesting biological activities as antimicrobial agents and enzyme inhibitors. We report in the present study a versatile synthesis of N-sulfenylated azetidinones starting from the corresponding N-bromo derivatives by means of the (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) radical as the catalyst and disulfides. Preparation of N-haloazetidinones was studied and optimized. The reactivity of N-bromo-azetidinone 2a as a model compound in the presence of TEMPO radical was investigated by NMR and electron paramagnetic resonance (EPR) spectroscopy studies. Optimization of the reaction conditions allowed the access of Nalkylthio-or N-arylthio-azetidinones from 55 to 92% yields, and the method exhibited a good substrate scope.

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N-Thio-β-lactams targeting L,D-transpeptidase-2, with activity against drug-resistant strains of Mycobacterium tuberculosis

Cited by 7 publications

References 66 publications

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

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

Innovative Strategies to Overcome Antimicrobial Resistance and Tolerance

N-Sulfenylation of β-Lactams: Radical Reaction of N-Bromo-azetidinones by TEMPO Catalysis

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