Spiropyrimidinetriones: a Class of DNA Gyrase Inhibitors with Activity against Mycobacterium tuberculosis and without Cross-Resistance to Fluoroquinolones

Basarab, Gregory S.; Ghorpade, Sandeep R.; Gibhard, Liezl; Mueller, Rudolf; Njoroge, Mathew; Peton, Nashied; Govender, Preshendren; Massoudi, Lisa M.; Robertson, Gregory T.; Lenaerts, Anne J.; Boshoff, Helena I.; Joerss, Douglas; Parish, Tanya; Durand-Réville, Thomas F.; Perros, Manos; Singh, Vinayak; Chibale, Kelly

doi:10.1128/aac.02192-21

Cited by 16 publications

(39 citation statements)

References 41 publications

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“…It is likely that there is a contribution to cidality associated with production of the cleaved DNA due to induction of the cellular hypersensitive SOS response. 24,48 Taken together with the hypomorph data, the MoIs for SPTs and FQs are similar in that they show bactericidal activity by inhibition of gyrase.…”

Section: Table 3 Data Formentioning

confidence: 72%

“…We have recently published an exploration of SPTs for the treatment of TB wherein activity was seen for a variety of analogues, including zoliflodacin and the methyloxadiazole analogue 5 of Figure . Compound 5 , which showed higher Mtb activity than zoliflodacin, demonstrated cidality against the pathogen, activity against FQ-resistant Mtb strains, and activity in a mouse infection model of TB …”

Section: Introductionmentioning

confidence: 99%

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Spiropyrimidinetrione DNA Gyrase Inhibitors with Potent and Selective Antituberculosis Activity

et al. 2022

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New antibiotics with either a novel mode-of-action (MoA) or novel mode-of-inhibition (MoI) are urgently needed to overcome the threat of drug-resistant tuberculosis (TB). The present study profiles new spiropyrimidinetriones (SPTs), DNA gyrase inhibitors having activity against drug resistant Mycobacterium tuberculosis (Mtb), the causative agent of TB. While the clinical candidate zoliflodacin has progressed to Phase 3 trials for the treatment of gonorrhea, compounds herein demonstrated higher inhibitory potency against Mtb DNA gyrase (e.g., Compound 42 with an IC50 = 2.0) and lower Mtb MICs (0.49 µM for 42). Notably, 42 and analogues showed selective Mtb activity relative to representative Gram-positive and Gram-negative bacteria. DNA gyrase inhibition was shown to involve stabilization of double-cleaved DNA while on-target activity was supported by hypersensitivity against a gyrA hypomorph. Finally, a docking model for SPTs with Mtb DNA gyrase was developed and a structural hypothesis was built for SAR expansion.

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Section: Table 3 Data Formentioning

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Spiropyrimidinetrione DNA Gyrase Inhibitors with Potent and Selective Antituberculosis Activity

et al. 2022

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“…Spiropyrimidinetrione analogues, obtained from Entasis Therapeutics, were accordingly screened against Mtb under various culture conditions. 37 Compound 15 displayed a range of MICs (1.7–5.2 μM; with the minimum bactericidal concentration being only 2-fold higher than its MIC) in different growth media, and the lack of cross-resistance to various antitubercular drug-resistant Mtb mutants underpins the importance of spiropyrimidinetriones for eventual stewardship to the clinic. Importantly, Mtb strains resistant to fluoroquinolones were fully susceptible to spiropyrimidinetriones; this is attributed to the spiropyrimidinetrione class operating via a novel mode of inhibition, which involves Mg 2+ -independent stabilization of the DNA cleavage-complex with DNA gyrase.…”

Section: Tuberculosismentioning

confidence: 99%

“…However, compound 15 exhibited a weaker MIC compared to moxifloxacin despite showing better DNA gyrase inhibition activity than moxifloxacin. 37 This guided us toward design efforts to optimize spiropyrimidinetrione bacterial permeability and target potency.…”

Section: Tuberculosismentioning

confidence: 99%

Innovation Experiences from Africa-Led Drug Discovery at the Holistic Drug Discovery and Development (H3D) Centre

Singh

Mambwe

Korkor

et al. 2022

ACS Med. Chem. Lett.

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As the so-called “next frontier” in global economic terms, Africa’s disease burden continues to choke and cripple economic growth across the continent. The highest burden is attributable to malaria and tuberculosis (TB), which also remain among the deadliest infectious diseases affecting mankind the world over (Malaria, 627,000 deaths; TB, 1.5 million deaths, in 2020). In achieving self-determination with respect to the health needs of all who live on the continent, Africa must align with global north efforts and be a source of health innovation. This will in part require the creation of an ecosystem of innovative pharmaceutical R&D and expanding it across the continent by scaling up through sustained performance and excellence. To this end, the Holistic Drug Discovery and Development (H3D) Centre at University of Cape Town in South Africa has risen to this challenge. Here, we highlight the innovation experiences gained at H3D, covering the advances made in our quest to contribute to a global pipeline of therapeutic interventions against malaria and TB. We discuss selected chemical series starting from their identification, structure–activity relationships, mode of action, safety, proof-of-concept studies, and lessons learned.

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“…Examples include the naphthyridone/aminopiperidines (Gibson et al, 2019) and alkoxytriazoloquinolones (Carta et al, 2019). The spiropyrimidinetrione series has activity against M. tuberculosis strains with mutations in gyrase suggesting a potential to overcome fluoroquinolone resistance (Basarab et al, 2022). In addition, the possibility of targeting GyrB has been addressed (Stokes et al, 2020); for example, the aminopyrazinamides and 2-amino-5-phenylthiophene-3- carboxamide (Shirude et al, 2013;Saxena et al, 2015) which target GyrB have good potency in vitro.…”

Section: New Gyrase Inhibitorsmentioning

confidence: 99%

How Mycobacterium tuberculosis drug resistance has shaped anti-tubercular drug discovery

Bhagwat

Deshpande²,

Parish³

2022

Front. Cell. Infect. Microbiol.

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Drug resistance is an increasing problem for the treatment of tuberculosis. The prevalence of clinical isolates with pre-existing resistance needs to be considered in any drug discovery program. Non-specific mechanisms of resistance such as increased efflux or decreased permeability need to be considered both in developing individual drug candidates and when designing novel regimens. We review a number of different approaches to develop new analogs and drug combinations or improve efficacy of existing drugs that may overcome or delay the appearance of clinical resistance. We also discuss the need to fully characterize mechanisms of resistance and cross- resistance to existing drugs to ensure that novel drugs will be clinically effective.

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Spiropyrimidinetriones: a Class of DNA Gyrase Inhibitors with Activity against Mycobacterium tuberculosis and without Cross-Resistance to Fluoroquinolones

Cited by 16 publications

References 41 publications

Spiropyrimidinetrione DNA Gyrase Inhibitors with Potent and Selective Antituberculosis Activity

Spiropyrimidinetrione DNA Gyrase Inhibitors with Potent and Selective Antituberculosis Activity

Innovation Experiences from Africa-Led Drug Discovery at the Holistic Drug Discovery and Development (H3D) Centre

How Mycobacterium tuberculosis drug resistance has shaped anti-tubercular drug discovery

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