Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Alfonso Mendoza-Losana is active.

Publication


Featured researches published by Alfonso Mendoza-Losana.


PLOS ONE | 2013

Tetrahydropyrazolo[1,5-a]Pyrimidine-3-Carboxamide and N-Benzyl-6′,7′-Dihydrospiro[Piperidine-4,4′-Thieno[3,2-c]Pyran] analogues with bactericidal efficacy against Mycobacterium tuberculosis targeting MmpL3

Modesto J. Remuiñán; Esther Pérez-Herrán; Joaquín Rullas; Carlos Alemparte; María Martínez-Hoyos; David J. Dow; Johnson Afari; Jorge Esquivias; Elena Jimenez; Fátima Ortega-Muro; María Teresa Fraile-Gabaldón; Vickey L. Spivey; Nicholas J. Loman; Mark J. Pallen; Chrystala Constantinidou; Douglas J. Minick; Mónica Cacho; María José Rebollo-López; Carolina González; Verónica Sousa; Iñigo Angulo-Barturen; Alfonso Mendoza-Losana; David Barros; Gurdyal S. Besra; Lluis Ballell; Nicholas Cammack

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. As part of our efforts towards the discovery of new anti-tubercular leads, a number of potent tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (THPP) and N-benzyl-6′,7′-dihydrospiro[piperidine-4,4′-thieno[3,2-c]pyran] (Spiro) analogues were recently identified against Mycobacterium tuberculosis and Mycobacterium bovis BCG through a high-throughput whole-cell screening campaign. Herein, we describe the attractive in vitro and in vivo anti-tubercular profiles of both lead series. The generation of M. tuberculosis spontaneous mutants and subsequent whole genome sequencing of several resistant mutants identified single mutations in the essential mmpL3 gene. This ‘genetic phenotype’ was further confirmed by a ‘chemical phenotype’, whereby M. bovis BCG treated with both the THPP and Spiro series resulted in the accumulation of trehalose monomycolate. In vivo efficacy evaluation of two optimized THPP and Spiro leads showed how the compounds were able to reduce >2 logs bacterial cfu counts in the lungs of infected mice.


Journal of Medicinal Chemistry | 2014

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

Lourdes Encinas; Heather O’Keefe; Margarete Neu; Modesto J. Remuiñán; Amish Patel; Ana Guardia; Christopher P. Davie; Natalia Pérez-Macías; Hongfang Yang; Jeff A. Messer; Esther Pérez-Herrán; Paolo A. Centrella; Daniel Álvarez-Gómez; Matthew A. Clark; Sophie Huss; Gary O’Donovan; Fátima Ortega-Muro; William McDowell; Pablo Castañeda; Christopher C. Arico-Muendel; Stane Pajk; Joaquín Rullas; Iñigo Angulo-Barturen; Emilio Alvarez-Ruiz; Alfonso Mendoza-Losana; Lluís Pagès; Julia Castro-Pichel; Ghotas Evindar

Tuberculosis (TB) is one of the worlds 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 infections caused by INH resistant strains. The application of the encoded library technology (ELT) to the discovery of direct InhA inhibitors yielded compound 7 endowed with good enzymatic potency but with low antitubercular potency. This work reports the hit identification, the selected strategy for potency optimization, the structure-activity relationships of a hundred analogues synthesized, and the results of the in vivo efficacy studies performed with the lead compound 65.


Antimicrobial Agents and Chemotherapy | 2012

Streptomycin-Starved Mycobacterium tuberculosis 18b, a Drug Discovery Tool for Latent Tuberculosis

Ming Zhang; Claudia Sala; Ruben C. Hartkoorn; Neeraj Dhar; Alfonso Mendoza-Losana; Stewart T. Cole

ABSTRACT Mycobacterium tuberculosis 18b, a streptomycin (STR)-dependent mutant that enters a viable but nonreplicating state in the absence of STR, has been developed as a simple model for drug testing against dormant bacilli. Here, we further evaluated the STR-starved 18b (SS18b) model both in vitro and in vivo by comparing the behavior of 22 approved and experimental tuberculosis drugs. Using the resazurin reduction microplate assay (REMA), rifampin (RIF), rifapentine (RPT), TMC207, clofazimine (CFM), and linezolid (LIN) were found to be active against SS18b in vitro, and their bactericidal activity was confirmed by determining the number of CFU. A latent 18b infection was established in mice, and some of the above-mentioned drugs were used for treatment, either alone or in combination with RIF. RIF, RPT, TMC207, CFM, and pyrazinamide (PZA) were all active in vivo, while cell wall inhibitors were not. A comparative kinetic study of rifamycin efficacy was then undertaken, and the results indicated that RPT clears latent 18b infection in mice faster than RIF. Intrigued by the opposing responses of live and dormant 18b cells to cell wall inhibitors, we conducted a systematic analysis of 14 such inhibitors using REMA. This uncovered an SS18b signature (CWPRED) that accurately predicted the activities of cell wall inhibitors and performed well in a blind study. CWPRED will be useful for establishing the mode of action of compounds with unknown targets, while the SS18b system should facilitate the discovery of drugs for treating latent tuberculosis.


Proceedings of the National Academy of Sciences of the United States of America | 2016

N-methylation of a bactericidal compound as a resistance mechanism in Mycobacterium tuberculosis.

Thulasi Warrier; Kanishk Kapilashrami; Argyrides Argyrou; Thomas R. Ioerger; David Little; Kenan C. Murphy; Madhumitha Nandakumar; Suna Park; Ben Gold; Jianjie Mi; Tuo Zhang; Eugenia Meiler; Mike Rees; Selin Somersan-Karakaya; Esther Porras-De Francisco; María Martínez-Hoyos; Kristin Burns-Huang; Julia Roberts; Yan Ling; Kyu Y. Rhee; Alfonso Mendoza-Losana; Minkui Luo; Carl Nathan

Significance Better understanding of the mechanisms used by bacteria to counter antibacterial agents is essential to cope with the rising prevalence of antimicrobial resistance. Here, we identified the mechanism of resistance of Mycobacterium tuberculosis to an antimycobacterial cyano-substituted fused pyrido-benzimidazole. Clones bearing mutations in a transcription factor, Rv2887, markedly up-regulated the expression of rv0560c, a putative methyltransferase. Rv0560c N-methylated the pyrido-benzimidazole in vitro and in Mycobacterium tuberculosis, abrogating its bactericidal activity. Resistant mutants selected in the absence of rv0560c led to the identification of the target of the compound, the essential oxidoreductase, decaprenylphosphoryl-β-d-ribose 2-oxidase (DprE1). Methylation of an antibacterial compound is a previously uncharacterized mode of antimicrobial resistance. The rising incidence of antimicrobial resistance (AMR) makes it imperative to understand the underlying mechanisms. Mycobacterium tuberculosis (Mtb) is the single leading cause of death from a bacterial pathogen and estimated to be the leading cause of death from AMR. A pyrido-benzimidazole, 14, was reported to have potent bactericidal activity against Mtb. Here, we isolated multiple Mtb clones resistant to 14. Each had mutations in the putative DNA-binding and dimerization domains of rv2887, a gene encoding a transcriptional repressor of the MarR family. The mutations in Rv2887 led to markedly increased expression of rv0560c. We characterized Rv0560c as an S-adenosyl-L-methionine-dependent methyltransferase that N-methylates 14, abolishing its mycobactericidal activity. An Mtb strain lacking rv0560c became resistant to 14 by mutating decaprenylphosphoryl-β-d-ribose 2-oxidase (DprE1), an essential enzyme in arabinogalactan synthesis; 14 proved to be a nanomolar inhibitor of DprE1, and methylation of 14 by Rv0560c abrogated this activity. Thus, 14 joins a growing list of DprE1 inhibitors that are potently mycobactericidal. Bacterial methylation of an antibacterial agent, 14, catalyzed by Rv0560c of Mtb, is a previously unreported mechanism of AMR.


ACS Infectious Diseases | 2015

Identification of Novel Anti-mycobacterial Compounds by Screening a Pharmaceutical Small-Molecule Library against Nonreplicating Mycobacterium tuberculosis

Thulasi Warrier; María Martínez-Hoyos; Manuel Marin-Amieva; Gonzalo Colmenarejo; Esther Porras-De Francisco; Ana Isabel Alvarez-Pedraglio; María Teresa Fraile-Gabaldón; Pedro Alfonso Torres-Gomez; Landys Lopez-Quezada; Ben Gold; Julia Roberts; Yan Ling; Selin Somersan-Karakaya; David Little; Nicholas Cammack; Carl Nathan; Alfonso Mendoza-Losana

Identification of compounds that target metabolically diverse subpopulations of Mycobacterium tuberculosis (Mtb) may contribute to shortening the course of treatment for tuberculosis. This study screened 270,000 compounds from GlaxoSmithKlines collection against Mtb in a nonreplicating (NR) state imposed in vitro by a combination of four host-relevant stresses. Evaluation of 166 confirmed hits led to detailed characterization of 19 compounds for potency, specificity, cytotoxicity, and stability. Compounds representing five scaffolds depended on reactive nitrogen species for selective activity against NR Mtb, and two were stable in the assay conditions. Four novel scaffolds with activity against replicating (R) Mtb were also identified. However, none of the 19 compounds was active against Mtb in both NR and R states. There was minimal overlap between compounds found active against NR Mtb and those previously identified as active against R Mtb, supporting the hypothesis that NR Mtb depends on distinct metabolic pathways for survival.


Scientific Reports | 2016

Repurposing clinically approved cephalosporins for tuberculosis therapy

Santiago Ramón-García; Rubén González del Río; Angel Santos Villarejo; Gaye Sweet; Fraser Cunningham; David Barros; Lluis Ballell; Alfonso Mendoza-Losana; Santiago Ferrer-Bazaga; Charles J. Thompson

While modern cephalosporins developed for broad spectrum antibacterial activities have never been pursued for tuberculosis (TB) therapy, we identified first generation cephalosporins having clinically relevant inhibitory concentrations, both alone and in synergistic drug combinations. Common chemical patterns required for activity against Mycobacterium tuberculosis were identified using structure-activity relationships (SAR) studies. Numerous cephalosporins were synergistic with rifampicin, the cornerstone drug for TB therapy, and ethambutol, a first-line anti-TB drug. Synergy was observed even under intracellular growth conditions where beta-lactams typically have limited activities. Cephalosporins and rifampicin were 4- to 64-fold more active in combination than either drug alone; however, limited synergy was observed with rifapentine or rifabutin. Clavulanate was a key synergistic partner in triple combinations. Cephalosporins (and other beta-lactams) together with clavulanate rescued the activity of rifampicin against a rifampicin resistant strain. Synergy was not due exclusively to increased rifampicin accumulation within the mycobacterial cells. Cephalosporins were also synergistic with new anti-TB drugs such as bedaquiline and delamanid. Studies will be needed to validate their in vivo activities. However, the fact that cephalosporins are orally bioavailable with good safety profiles, together with their anti-mycobacterial activities reported here, suggest that they could be repurposed within new combinatorial TB therapies.


EBioMedicine | 2016

Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor

María Martínez-Hoyos; Esther Pérez-Herrán; Gulcin Gulten; Lourdes Encinas; Daniel Álvarez-Gómez; Emilio Alvarez; Santiago Ferrer-Bazaga; Adolfo García-Pérez; Fátima Ortega; Iñigo Angulo-Barturen; Joaquin Rullas-Trincado; Delia Blanco Ruano; Pedro Torres; Pablo Castañeda; Sophie Huss; Raquel Fernández Menéndez; Silvia González del Valle; Lluis Ballell; David Barros; Sundip Modha; Neeraj Dhar; François Signorino-Gelo; John D. McKinney; Jose Garcia-Bustos; Jose Luis Lavandera; James C. Sacchettini; M. Soledad Jimenez; Nuria Martín-Casabona; Julia Castro-Pichel; Alfonso Mendoza-Losana

Despite being one of the first antitubercular agents identified, isoniazid (INH) is still the most prescribed drug for prophylaxis and tuberculosis (TB) treatment and, together with rifampicin, the pillars of current chemotherapy. A high percentage of isoniazid resistance is linked to mutations in the pro-drug activating enzyme KatG, so the discovery of direct inhibitors (DI) of the enoyl-ACP reductase (InhA) has been pursued by many groups leading to the identification of different enzyme inhibitors, active against Mycobacterium tuberculosis (Mtb), but with poor physicochemical properties to be considered as preclinical candidates. Here, we present a series of InhA DI active against multidrug (MDR) and extensively (XDR) drug-resistant clinical isolates as well as in TB murine models when orally dosed that can be a promising foundation for a future treatment.


PLOS ONE | 2015

Release of 50 new, drug-like compounds and their computational target predictions for open source anti-tubercular drug discovery.

María José Rebollo-López; Joël Lelièvre; Daniel Álvarez-Gómez; Julia Castro-Pichel; Francisco Martínez-Jiménez; George Papadatos; Vinod Kumar; Gonzalo Colmenarejo; Grace Mugumbate; Mark R. Hurle; Vanessa Barroso; Robert J. Young; María Martínez-Hoyos; Rubén González del Río; Robert H. Bates; Eva Maria Lopez-Roman; Alfonso Mendoza-Losana; James R. Brown; Emilio Alvarez-Ruiz; Marc A. Marti-Renom; John P. Overington; Nicholas Cammack; Lluis Ballell; David Barros-Aguire

As a follow up to the antimycobacterial screening exercise and the release of GSK´s first Tres Cantos Antimycobacterial Set (TCAMS-TB), this paper presents the results of a second antitubercular screening effort of two hundred and fifty thousand compounds recently added to the GSK collection. The compounds were further prioritized based on not only antitubercular potency but also on physicochemical characteristics. The 50 most attractive compounds were then progressed for evaluation in three different predictive computational biology algorithms based on structural similarity or GSK historical biological assay data in order to determine their possible mechanisms of action. This effort has resulted in the identification of novel compounds and their hypothesized targets that will hopefully fuel future TB drug discovery and target validation programs alike.


Molecular and Biochemical Parasitology | 2012

A new molecular approach for cidal vs static antimalarial determination by quantifying mRNA levels.

Noemí Bahamontes-Rosa; Ane Rodríguez-Alejandre; Rubén González-del-Rio; Jose Garcia-Bustos; Alfonso Mendoza-Losana

In order to maximise compliance, the future antimalarial treatment should ideally require just a single-dose administration. This, in turn, demands new fast-acting effective drugs. Currently, methods to measure the in vitro killing rate of antimalarials are based on parasite growth. We have developed and validated a method to determine and classify antimalarial agents based on their cidal or static activity following quantitative Real Time PCR (RT-PCR) analysis. The method described here is a fast, reliable and user-friendly technique with a medium throughput. Metabolic activity of the parasite is followed by measuring mRNA expression levels of several genes during 5 parasite life cycles. mRNA from the parasite culture is then retrotranscribed to cDNA and quantified by RT-PCR. This new method provides a rapid and reproducible way to accurately measure the antimalarial activity of new compounds in vitro against Plasmodium falciparum.


Journal of Medicinal Chemistry | 2017

Discovery of a Potent and Specific M. tuberculosis Leucyl-tRNA Synthetase Inhibitor: (S)-3-(Aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1,2]oxaborol-1(3H)-ol (GSK656)

Xianfeng Li; Vincent Hernandez; Fernando Rock; Wai Choi; Yvonne Mak; Manisha Mohan; Weimin Mao; Yasheen Zhou; Eric E. Easom; Jacob J. Plattner; Wuxin Zou; Esther Pérez-Herrán; Ilaria Giordano; Alfonso Mendoza-Losana; Carlos Alemparte; Joaquín Rullas; Iñigo Angulo-Barturen; Sabrinia Crouch; Fátima Ortega; David Barros; M. R. K. Alley

There is an urgent need to develop new and safer antitubercular agents that possess a novel mode of action. We synthesized and evaluated a novel series of 3-aminomethyl 4-halogen benzoxaboroles as Mycobacterium tuberculosis (Mtb) leucyl-tRNA synthetase (LeuRS) inhibitors. A number of Mtb LeuRS inhibitors were identified that demonstrated good antitubercular activity with high selectivity over human mitochondrial and cytoplasmic LeuRS. Further evaluation of these Mtb LeuRS inhibitors by in vivo pharmacokinetics (PK) and murine tuberculosis (TB) efficacy models led to the discovery of GSK3036656 (abbreviated as GSK656). This molecule shows potent inhibition of Mtb LeuRS (IC50 = 0.20 μM) and in vitro antitubercular activity (Mtb H37Rv MIC = 0.08 μM). Additionally, it is highly selective for the Mtb LeuRS enzyme with IC50 of >300 μM and 132 μM for human mitochondrial LeuRS and human cytoplasmic LeuRS, respectively. In addition, it exhibits remarkable PK profiles and efficacy against Mtb in mouse TB infection models with superior tolerability over initial leads. This compound has been progressed to clinical development for the treatment of tuberculosis.

Collaboration


Dive into the Alfonso Mendoza-Losana's collaboration.

Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Researchain Logo
Decentralizing Knowledge