New potential drug leads against MDR-MTB: A short review

Gatadi, Srikanth; Nanduri, Srinivas

doi:10.1016/j.bioorg.2019.103534

Cited by 19 publications

(8 citation statements)

References 98 publications

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“…, Pfizer, AstraZeneca, and Novartis), , in the past two decades, the development of new drugs for TB has recaptured substantial global interest, resulting in the identification of many new lead candidates. Many reviews have been published addressing novel compounds with potent in vitro activity in the early stages of development (discovery), ,− and others have described the drug candidates in clinical studies. ,, Nevertheless, there is a scarcity of reviews covering the anti-TB compounds that have progressed to “validated lead” or preclinical development status, and, to the best of our knowledge, no article to date has specifically covered those compounds from a drug candidate profiling perspective. This section reviews the anti-TB compounds published in the last 6 years that have reached such stages (arising from hit-to-lead, lead optimization, and other preclinical investigations), focusing solely on those with proven efficacy against Mtb in animal models.…”

Section: Preclinical Promisesmentioning

confidence: 99%

Tuberculosis Drug Discovery: Challenges and New Horizons

et al. 2022

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Over the past 2000 years, tuberculosis (TB) has claimed more lives than any other infectious disease. In 2020 alone, TB was responsible for 1.5 million deaths worldwide, comparable to the 1.8 million deaths caused by COVID-19. The World Health Organization has stated that new TB drugs must be developed to end this pandemic. After decades of neglect in this field, a renaissance era of TB drug discovery has arrived, in which many novel candidates have entered clinical trials. However, while hundreds of molecules are reported annually as promising anti-TB agents, very few successfully progress to clinical development. In this Perspective, we critically review those anti-TB compounds published in the last 6 years that demonstrate good in vivo efficacy against Mycobacterium tuberculosis. Additionally, we highlight the main challenges and strategies for developing new TB drugs and the current global pipeline of drug candidates in clinical studies to foment fresh research perspectives.

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Section: Preclinical Promisesmentioning

confidence: 99%

Tuberculosis Drug Discovery: Challenges and New Horizons

et al. 2022

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“…It bound to PBP2a at the allosteric site as seen by crystallographic analysis . Related quinazolinone structures are active against both MSSA and Mycobacterium tuberculosis (such as 14 ), − and scaffold-hopping (from a nitroquinazolinone) gave thieno[3,2- d ]pyrimidin-4(3 H )-one structures (exemplified by 15 ) that were active against Clostridioides difficile . Phenyl substitution at N-3 in this structure was disadvantageous.…”

Section: Resistance Mechanisms Of S Aureus Against the β-Lactamsmentioning

confidence: 96%

β-Lactams against the Fortress of the Gram-Positive Staphylococcus aureus Bacterium

Fisher

Mobashery

2020

Chem. Rev.

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The biological diversity of the unicellular bacteriawhether assessed by shape, food, metabolism, or ecological nichesurely rivals (if not exceeds) that of the multicellular eukaryotes. The relationship between bacteria whose ecological niche is the eukaryote, and the eukaryote, is often symbiosis or stasis. Some bacteria, however, seek advantage in this relationship. One of the most successfulto the disadvantage of the eukaryoteis the small (less than 1 μm diameter) and nearly spherical Staphylococcus aureus bacterium. For decades, successful clinical control of its infection has been accomplished using β-lactam antibiotics such as the penicillins and the cephalosporins. Over these same decades S. aureus has perfected resistance mechanisms against these antibiotics, which are then countered by new generations of β-lactam structure. This review addresses the current breadth of biochemical and microbiological efforts to preserve the future of the β-lactam antibiotics through a better understanding of how S. aureus protects the enzyme targets of the β-lactams, the penicillin-binding proteins. The penicillin-binding proteins are essential enzyme catalysts for the biosynthesis of the cell wall, and understanding how this cell wall is integrated into the protective cell envelope of the bacterium may identify new antibacterials and new adjuvants that preserve the efficacy of the β-lactams.

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“…They exhibit in vivo activity in two mouse models of MRSA infection. ,,− In these cases, inhibition of PBP activity was documented by fluorescence assays, by antagonizing chemical–genetic interactions by antisense methodology and by X-ray crystallography in two cases (discussed below). The antibacterial oxadiazoles and quinazolinones have been studied recently by other laboratories. − …”

Section: The Discovery Paradigmmentioning

confidence: 99%

Unconventional Antibacterials and Adjuvants

et al. 2021

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Conspectus The need for new classes of antibacterials is genuine in light of the dearth of clinical options for the treatment of bacterial infections. The prodigious discoveries of antibiotics during the 1940s to 1970s, a period wistfully referred to as the Golden Age of Antibiotics, have not kept up in the face of emergence of resistant bacteria in the past few decades. There has been a renewed interest in old drugs, the repurposing of the existing antibiotics and pairing of synergistic antibiotics or of an antibiotic with an adjuvant. Notwithstanding, discoveries of novel classes of these life-saving drugs have become increasingly difficult, calling for new paradigms. We describe, herein, three strategies from our laboratories toward discoveries of new antibacterials and adjuvants using computational and multidisciplinary experimental methods. One approach targets penicillin-binding proteins (PBPs), biosynthetic enzymes of cell-wall peptidoglycan, for discoveries of non-β-lactam inhibitors. Oxadiazoles and quinazolinones emerged as two structural classes out of these efforts. Several hundred analogs of these two classes of antibiotics have been synthesized and fully characterized in our laboratories. A second approach ventures into inhibition of allosteric regulation of cell-wall biosynthesis. The mechanistic details of allosteric regulation of PBP2a of Staphylococcus aureus, discovered in our laboratories, is outlined. The allosteric site in this protein is at 60 Å distance to the active site, whereby ligand binding at the former makes access to the latter by the substrate possible. We have documented that both quinazolinones and ceftaroline, a fifth-generation cephalosporin, bind to the allosteric site in manifestation of the antibacterial activity. Attempts at inhibition of the regulatory phosphorylation events identified three classes of antibacterial adjuvants and one class of antibacterials, the picolinamides. The chemical structures for these hits went through diversification by synthesis of hundreds of analogs. These analogs were characterized in various assays for identification of leads with adjuvant and antibacterial activities. Furthermore, we revisited the mechanism of bulgecins, a class of adjuvants discovered and abandoned in the 1980s. These compounds potentiate the activities of β-lactam antibiotics by the formation of bulges at the sites of septum formation during bacterial replication, which are points of structural weakness in the envelope. These bulges experience rupture, which leads to bacterial death. Bulgecin A inhibits the lytic transglycosylase Slt of Pseudomonas aeruginosa as a likely transition-state mimetic for its turnover of the cell-wall peptidoglycan. Once damage to cell wall is inflicted by a β-lactam antibiotic, the function of Slt is to repair the damage. When Slt is inhibited by bulgecin A, the organism cannot cope with it and would undergo rapid lysis. Bulgecin A is an effective adjuvant of β-lactam antibiotics. These discoveries of small-molecule classes of antibacterials ...

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New potential drug leads against MDR-MTB: A short review

Cited by 19 publications

References 98 publications

Tuberculosis Drug Discovery: Challenges and New Horizons

Tuberculosis Drug Discovery: Challenges and New Horizons

β-Lactams against the Fortress of the Gram-Positive Staphylococcus aureus Bacterium

Unconventional Antibacterials and Adjuvants

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