Genetic and chemical validation identifies Mycobacterium tuberculosis topoisomerase I as an attractive anti-tubercular target

Ravishankar, Sudha; Ambady, Anisha; Awasthy, Disha; Mudugal, Naina Vinay; Menasinakai, Sreenivasaiah; Jatheendranath, Sandesh; Guptha, Supreeth; Sharma, Sreevalli; Balakrishnan, Gayathri; Nandishaiah, Radha; Ramachandran, Vasanthi; Eyermann, Charles J.; Reck, Folkert; Rudrapatna, Suresh; Sambandamurthy, Vasan K.; Sharma, Uday

doi:10.1016/j.tube.2015.05.004

Cited by 42 publications

(47 citation statements)

References 58 publications

(68 reference statements)

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“…112 Através de uma triagem de uma biblioteca de 1500 compostos da empresa AstraZeneca, foi identificada a molécula dihidrobenzofuranil ureia (43) como inibidora da enzima Topo I (Figura 16) com valor de IC 50 igual a 60 μmol L -1 . 113 …”

Section: Dna Girase E Topoisomerase Iunclassified

Potenciais alvos moleculares para o desenvolvimento de novos fármacos antituberculose

2017

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POTENTIAL MOLECULAR TARGETS FOR ANTITUBERCULOSIS DRUG DISCOVERY. Tuberculosis (TB) is an infectious disease caused by mycobacteria from the Mycobacterium genus, mainly by Mycobacterium tuberculosis (MTB). The World HealthOrganization (WHO) aims to reduce the number of TB cases worldwide in the coming years. Nevertheless, the increasing number of multidrug-resistant (MDR-TB) and extensive-drug resistance (XDR-TB) strains, and the ineffectiveness of the current treatment in latent tuberculosis are challenges to be overcome. In this review, we will demonstrate the recent advances in the tuberculosis drug discovery, focusing the research of new molecular targets in the Mycobacterium tuberculosis. Among the promising targets described herein, we highlight those, which act in different pathways in the mycobacteria, such as energy metabolism, cell wall biosynthesis, DNA synthesis, iron metabolism and transport through membranes. Furthermore, bioactive compounds discovered using phenotypic assays screening and validated through genetic approaches are also presented.Keywords: medicinal chemistry; tuberculosis; Mycobacterium tuberculosis; molecular targets; new drugs. INTRODUÇÃOA tuberculose (TB) é uma doença infecciosa causada por micobactérias do complexo Mycobacterium, no entanto, a espécie responsável pelo maior número de casos de morbidade e mortalidade é o Mycobacterium tuberculosis (MTB). 1 Ocupando o ranking mundial como a principal causa de mortes causadas por doenças infecciosas, nos últimos anos a tuberculose ultrapassou, em número de casos, a infecção causada pelo vírus da imunodeficiência humana (HIV). 2,3 O último levantamento realizado em 2015 pela Organização Mundial da Saúde (OMS) apontou 9.6 milhões de novos casos no mundo e 1.5 milhões de mortes causadas pela doença. 3 Somado a esses dados, o surgimento e aumento de cepas de M. tuberculosis multirresistente aos fármacos (MDR-TB) e extensivamente resistente aos fármacos (XDR-TB) vêm alarmando as autoridades de todo o mundo. Essas formas de tuberculose apresentam baixas taxas de cura e maiores taxas de mortalidade devido às dificuldades de tratamento. 4 Além disso, já foram relatados na clínica casos de tuberculose totalmente resistente aos fármacos (TDR-TB). 5,6 Ao longo dos últimos anos, é possível constatar algumas evoluções no desenvolvimento de compostos candidatos a fármacos que possam atuar contra a TB. 7 Após um intervalo de mais de 50 anos sem novos medicamentos para o tratamento da TB, a bedaquilina foi aprovada em 2012 pela agência norte-americana U.S. Food and Drug Administration (FDA) para o tratamento de MDR-TB. Atualmente, diversos candidatos a fármacos estão em estudos clínicos, [8][9][10][11][12] 39 Atualmente, diversos métodos e estratégias são utilizados para o desenvolvimento de novos fármacos contra a TB, como por exemplo: 1) abordagens genéticas para identificação de novos alvos; 2) ensaios de triagem em larga escala utilizando a micobactéria como plataforma; 3) ferramentas de biologia estrutural e triagem virtual e; 4) modificações ...

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Section: Dna Girase E Topoisomerase Iunclassified

Potenciais alvos moleculares para o desenvolvimento de novos fármacos antituberculose

2017

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“…The bactericidal action of a topoisomerase I poison would not require that the topoisomerase I function be absolutely essential for viability. The consequences of loss of topoisomerase I function from topA mutation are different in different bacterial species [88][89][90][91][92]. For E. coli, topA deletion mutants are viable, but suppression of topB coding for topoisomerase III in ΔtopA background has been shown to be lethal [93].…”

Section: Bacterial Topoisomerase I Inhibitorsmentioning

confidence: 99%

“…There is a great need for new TB drugs against a novel target due to the problem with MDR-and XDR-TB that have added resistance to second-line TB drugs including fluoroquinolones [11]. M. tuberculosis topoisomerase I has been demonstrated recently to be essential for growth [90,91], and validated as an attractive antitubercular target [91]. Depletion of topoisomerase I resulted in clearing of bacilli in a mouse TB model [91].…”

Section: Bacterial Topoisomerase I Inhibitorsmentioning

confidence: 99%

“…M. tuberculosis topoisomerase I has been demonstrated recently to be essential for growth [90,91], and validated as an attractive antitubercular target [91]. Depletion of topoisomerase I resulted in clearing of bacilli in a mouse TB model [91]. Identification of potent and selective inhibitors of M. tuberculosis topoisomerase I could potentially provide new therapeutics for treatment of drug-resistant TB.…”

Section: Bacterial Topoisomerase I Inhibitorsmentioning

confidence: 99%

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Targeting Bacterial Topoisomerases: How to Counter Mechanisms of Resistance

Tse‐Dinh

2016

Future Med. Chem.

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DNA gyrase and topoisomerase IV are type IIA bacterial topoisomerases that are targeted by highly effective antibiotics. However, resistance via multiple mechanisms arises to limit the efficacies of these drugs. Continued research on type IIA bacterial topoisomerases has provided novel approaches to counter the most common resistance mechanism for utilization of these proven targets in antibacterial therapy. Bacterial topoisomerase I is being explored as an alternative target that is not expected to show cross-resistance. Dual targeting or combination therapy could be strategies for circumventing the development of resistance to topoisomerase-targeting antibiotics. Bacterial topoisomerases are high-value bactericidal targets that could continue to be exploited for antibacterial therapy, if new tactics to counter resistance can be adopted.

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“…There is only one type IA topoisomerase encoded by the genomes of mycobacteria. Mycobacterium tuberculosis topoisomerase I (MtbTopI) has been demonstrated in genetic studies to be essential for viability in vitro (24,25) and in vivo (25). Experimental data showed that the MIC of select small molecules against M. tuberculosis can be shifted by overexpression of topoisomerase I (25,26), further validating topoisomerase I as a vulnerable target in M. tuberculosis for chemical inhibition.…”

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confidence: 99%

Small-Molecule Inhibitors Targeting Topoisomerase I as Novel Antituberculosis Agents

Sandhaus

Annamalai

Welmaker

et al. 2016

Antimicrob Agents Chemother

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Genetic and chemical validation identifies Mycobacterium tuberculosis topoisomerase I as an attractive anti-tubercular target

Cited by 42 publications

References 58 publications

Potenciais alvos moleculares para o desenvolvimento de novos fármacos antituberculose

Potenciais alvos moleculares para o desenvolvimento de novos fármacos antituberculose

Targeting Bacterial Topoisomerases: How to Counter Mechanisms of Resistance

Small-Molecule Inhibitors Targeting Topoisomerase I as Novel Antituberculosis Agents

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