Encoded Library Technology as a Source of Hits for the Discovery and Lead Optimization of a Potent and Selective Class of Bactericidal Direct Inhibitors of Mycobacterium tuberculosis InhA

Authored by: Lourdes Encinas ‡, Heather O’Keefe †, Margarete Neu §, Modesto J. Remuiñán ‡, Amish M. Patel †, Ana Guardia ‡, Christopher P. Davie †, Natalia Pérez-Macías , Hongfang Yang †, Maire A. Convery §, Jeff A. Messer †, Esther Pérez-Herrán ‡, Paolo A. Centrella , Daniel Álvarez-Gómez ‡, Matthew A. Clark , Sophie Huss ‡, Gary K. O’Donovan †, Fátima Ortega-Muro ‡, William McDowell #, Pablo Castañeda ‡, Christopher C. Arico-Muendel †, Stane Pajk ∞, Joaquín Rullás ‡, Iñigo Angulo-Barturen ‡, Emilio Álvarez-Ruíz ×, Alfonso Mendoza-Losana ‡, Lluís Ballell Pages ‡, Julia Castro-Pichel *‡, and Ghotas Evindar *†

  Tuberculosis (TB) is one of the world’s oldest and deadliest diseases, killing a person every 20 s. InhA, the enoyl-ACP reductase from Mycobacterium tuberculosis, is the target of the frontline antitubercular drug isoniazid (INH). Compounds that directly target InhA and do not require activation by mycobacterial catalase peroxidase KatG are promising candidates for treating

Mesoporous silica particles potentiate antigen-specific T-cell responses

Authored by: Natalia Kupferschmidt​‌, Khaleda Rahman Qazi, Cecilia Kemi​‌, Helen Vallhov​, Alfonso E Garcia-Bennett​‌, Susanne Gabrielsson​‌ & Annika Scheynius​‌*

  Aim: To study the adjuvant effect of mesoporous silica particles and their capability of modifying an already existing allergic Th2-like immune response. Materials & methods: The adjuvant effect of Santa Barbara Amorphous-15 (SBA-15) mesoporous silica particles was studied in an antigen-specific ovalbumin (OVA) system in vitro and in vivo. The capacity of the OVA-loaded

Synthesis, toxicology and potential of ordered mesoporous materials in nanomedicine

Authored by: Garcia-Bennett, A.

Although ordered mesoporous silica materials have been studied for almost 20 years, their utilization within life science applications is relatively new and unexplored. An increasing number of researchers are transcending their respective fields in order to bridge the knowledge gap between materials chemistry and biotechnology, and to exploit the potential of mesoporous materials. Their intricate

In Vitro Cross-Linking of Mycobacterium tuberculosis Peptidoglycan by L,D-Transpeptidases and Inactivation of These Enzymes by Carbapenems

Authored by: Cordillot M, Dubée V, Triboulet S, Dubost L, Marie A, Hugonnet JE, Arthur M, Mainardi JL

The Mycobacterium tuberculosis peptidoglycan is cross-linked mainly by l,d-transpeptidases (LDTs), which are efficiently inactivated by a single β-lactam class, the carbapenems. Development of carbapenems for tuberculosis treatment has recently raised considerable interest since these drugs, in association with the β-lactamase inhibitor clavulanic acid, are uniformly active against extensively drug-resistant M. tuberculosis and kill both exponentially

Characterization of broad-spectrum Mycobacterium abscessus class A β-lactamase

Authored by: Soroka D, Dubée V, Soulier-Escrihuela O, Cuinet G, Hugonnet JE, Gutmann L, Mainardi JL, Arthur M

Imipenem and cefoxitin are used to treat Mycobacterium abscessus infections and have moderate activity against this fast-growing mycobacterium (MIC50 of 16 and 32 mg/L, respectively). M. abscessus is highly resistant to most other β-lactams, although the underlying mechanisms have not been explored. Here, we characterized M. abscessus class A β-lactamase (BlaMab) and investigated its role

Kinetic Features of L,D-Transpeptidase Inactivation Critical for β-Lactam Antibacterial Activity

Authored by: Sébastien Triboulet equal contributor, equal contributor Contributed equally to this work with: Sébastien Triboulet, Vincent Dubée Sébastien Triboulet, Vincent Dubée

Active-site serine D,D-transpeptidases belonging to the penicillin-binding protein family (PBPs) have been considered for a long time as essential for peptidoglycan cross-linking in all bacteria. However, bypass of the PBPs by an L,D-transpeptidase (Ldtfm) conveys high-level resistance to β-lactams of the penam class in Enterococcus faecium with a minimal inhibitory concentration (MIC) of ampicillin >2,000


Improved BM212 MmpL3 Inhibitor Analogue Shows Efficacy in Acute Murine Model of Tuberculosis Infection

Authored by: Poce G, Bates RH, Alfonso S, Cocozza M, Porretta GC, Ballell L, Rullas J, Ortega F, De Logu A, Agus E, La Rosa V, Pasca MR, De Rossi E, Wae B, Franzblau SG, Manetti F, Botta M, Biava M. Publication: PLoS One. 2013;8(2):e56980. doi: 10.1371/journal.pone.0056980. Epub 2013 Feb 21.

1,5-Diphenyl pyrroles were previously identified as a class of compounds endowed with high in vitro efficacy against M. tuberculosis.


Fueling open-source drug discovery: 177 small-molecule leads against tuberculosis

Authored by: Ballell L, Bates RH, Young RJ, Alvarez-Gomez D, Alvarez-Ruiz E, Barroso V, Blanco D, Crespo B, Escribano J, González R, Lozano S, Huss S, Santos-Villarejo A, Martín-Plaza JJ, Mendoza A, Rebollo-Lopez MJ, Remuiñan-Blanco M, Lavandera JL, Pérez-Herran E, Gamo-Benito FJ, García-Bustos JF, Barros D, Castro JP, Cammack N. Publication: ChemMedChem. 2013 Feb;8(2):313-21. doi: 10.1002/cmdc.201200428. Epub 2013 Jan 10.

With the aim of fuelling open-source, translational, early-stage drug discovery activities, the results of the recently completed antimycobacterial phenotypic screening campaign against Mycobacterium bovis BCG with hit confirmation in M. tuberculosis H37Rv were made publicly accessible. A set of 177 potent non-cytotoxic H37Rv hits was identified and will be made available to maximize the potential


Identification of novel imidazo[1,2-a]pyridine inhibitors targeting M. tuberculosis QcrB

Authored by: Abrahams KA, Cox JA, Spivey VL, Loman NJ, Pallen MJ, Constantinidou C, Fernández R, Alemparte C, Remuiñán MJ, Barros D, Ballell L, Besra GS. Publication: PLoS One. 2012;7(12):e52951. doi: 10.1371/journal.pone.0052951. Epub 2012 Dec 31.

Mycobacterium tuberculosis is a major human pathogen and the causative agent for the pulmonary disease, tuberculosis (TB). Current treatment programs to combat TB are under threat due to the emergence of multi-drug and extensively-drug resistant TB. Through the use of high throughput whole cell screening of an extensive compound library a number of imidazo[1,2-a]pyridine (IP)


Russian “successful” clone B0/W148 of Mycobacterium tuberculosis Beijing genotype: a multiplex PCR assay for rapid detection and global screening

Authored by: Mokrousov I, Narvskaya O, Vyazovaya A, Otten T, Jiao WW, Gomes LL, Suffys PN, Shen AD, Vishnevsky B. Publication: Journal of Clinical Microbiology, Vol. 50, issue 11

We describe a multiplex PCR assay to detect the Mycobacterium tuberculosis Beijing genotype variant B0/W148, which is considered a “successful” clone of M. tuberculosis, widespread in Russia.