Optimising in situ click chemistry: the screening and identification of biotin protein ligase inhibitors

A 'leaky mutant' (SaBPL-R122G) of Staphylococcus aureus biotin protein ligase (SaBPL) is used to enhance the turnover rate for the reaction of biotin alkyne with an azide to give a triazole. This allows the enzyme to select the optimum triazole-based inhibitor using a library of such azides in a single experiment with greatly improved efficiency and sensitivity of detection, difficulties that can restrict the general utility of a multi-component in situ click approach to ligand optimisation. © 2013 The Royal Society of Chemistry.William Tieu, Tatiana P. Soares da Costa, Min Y. Yap, Kelly L. Keeling, Matthew C. J. Wilce, John C. Wallace, Grant W. Booker, Steven W. Polyak and Andrew D. Abel

Optimization of pyridylpiperazine-based inhibitors of the Escherichia coli AcrAB-TolC efflux pump

Multidrug–resistant Escherichia coli is a continuously growing worldwide public health problem, in which the well-known AcrAB-TolC tripartite RND efflux pump is a critical driver. We have previously described pyridylpiperazines as a novel class of allosteric inhibitors of E. coli AcrB which bind to a unique site in the protein transmembrane domain, allowing for the potentiation of antibiotic activity. Here, we show a rational optimization of pyridylpiperazines by modifying three specific derivatization points of the pyridine core to improve the potency and the pharmacokinetic properties of this chemical series. In particular, this work found that the introduction of a primary amine to the pyridine through ester (29, BDM91270) or oxadiazole (44, BDM91514) based linkers allowed for analogues with improved antibiotic boosting potency through AcrB inhibition. In vitro studies, using genetically engineered mutants, showed that this improvement in potency is mediated through novel interactions with distal acidic residues of the AcrB binding pocket. Of the two leads, compound 44 was found to have favorable physico-chemical properties and suitable plasma and microsomal stability. Together, this work expands the current structure-activity relationship data on pyridylpiperazine efflux pump inhibitors, and provides a promising step towards future in vivo proof of concept of pyridylpiperazines as antibiotic potentiators

On the Hunt for Next-Generation Antimicrobial Agents: An Online Symposium Organized Jointly by the French Society for Medicinal Chemistry (Société de Chimie Thérapeutique) and the French Microbiology Society (Société Française de Microbiologie) on 9–10 December 2021

The restrictions posed by the COVID-19 pandemic obliged the French Society for Medicinal Chemistry (Société de chimie thérapeutique) and the French Microbiology Society (Société Française de Microbiologie) to organize their joint autumn symposium (entitled “On the hunt for next-generation antimicrobial agents”) online on 9–10 December 2021. The meeting attracted more than 200 researchers from France and abroad with interests in drug discovery, antimicrobial resistance, medicinal chemistry, and related disciplines. This review summarizes the 13 invited keynote lectures. The symposium generated high-level scientific dialogue on the most recent advances in combating antimicrobial resistance. The University of Lille, the Institut Pasteur de Lille, the journal Pharmaceuticals, Oxeltis, and INCATE, sponsored the event.</jats:p

On the Hunt for Next-Generation Antimicrobial Agents: An Online Symposium Organized Jointly by the French Society for Medicinal Chemistry (Soci&eacute;t&eacute; de Chimie Th&eacute;rapeutique) and the French Microbiology Society (Soci&eacute;t&eacute; Fran&ccedil;aise de Microbiologie) on 9&ndash;10 December 2021

The restrictions posed by the COVID-19 pandemic obliged the French Society for Medicinal Chemistry (Soci&eacute;t&eacute; de chimie th&eacute;rapeutique) and the French Microbiology Society (Soci&eacute;t&eacute; Fran&ccedil;aise de Microbiologie) to organize their joint autumn symposium (entitled &ldquo;On the hunt for next-generation antimicrobial agents&rdquo;) online on 9&ndash;10 December 2021. The meeting attracted more than 200 researchers from France and abroad with interests in drug discovery, antimicrobial resistance, medicinal chemistry, and related disciplines. This review summarizes the 13 invited keynote lectures. The symposium generated high-level scientific dialogue on the most recent advances in combating antimicrobial resistance. The University of Lille, the Institut Pasteur de Lille, the journal Pharmaceuticals, Oxeltis, and INCATE, sponsored the event

Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps

Efflux transporters of the RND family confer resistance to multiple antibiotics in Gram-negative bacteria. Here, we identify and chemically optimize pyridylpiperazine-based compounds that potentiate antibiotic activity in E. coli through inhibition of its primary RND transporter, AcrAB-TolC. Characterisation of resistant E. coli mutants and structural biology analyses indicate that the compounds bind to a unique site on the transmembrane domain of the AcrB L protomer, lined by key catalytic residues involved in proton relay. Molecular dynamics simulations suggest that the inhibitors access this binding pocket from the cytoplasm via a channel exclusively present in the AcrB L protomer. Thus, our work unveils a class of allosteric efflux-pump inhibitors that likely act by preventing the functional catalytic cycle of the RND pump

Recent advances in the design of inhibitors of mycobacterial transcriptional regulators to boost thioamides anti-tubercular activity and circumvent acquired-resistance

International audienc

Pyridylpiperazine-based allosteric inhibitors of RND-type multidrug efflux pumps

AbstractEfflux transporters of the RND family confer resistance to multiple antibiotics in Gram-negative bacteria. Here, we identify and chemically optimize pyridylpiperazine-based compounds that potentiate antibiotic activity in E. coli through inhibition of its primary RND transporter, AcrAB-TolC. Characterisation of resistant E. coli mutants and structural biology analyses indicate that the compounds bind to a unique site on the transmembrane domain of the AcrB L protomer, lined by key catalytic residues involved in proton relay. Molecular dynamics simulations suggest that the inhibitors access this binding pocket from the cytoplasm via a channel exclusively present in the AcrB L protomer. Thus, our work unveils a class of allosteric efflux-pump inhibitors that likely act by preventing the functional catalytic cycle of the RND pump.</jats:p