Mycobacterial Membrane Protein Large 3 (MmpL3) Inhibitors: A Promising Approach to Combat Tuberculosis

Umare, Mohit D.; Khedekar, Pramod B.; Chikhale, Rupesh

doi:10.1002/cmdc.202100359

Cited by 33 publications

(23 citation statements)

References 57 publications

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“…Until recently, docking of the MmpL3 inhibitors was performed on the M. tuberculosis MmpL3 homology model. The diverse inhibitors of MmpL3 previously identified are known to target the proton translocation path in the channel of transmembrane segment of MmpL3 [ 35 , 44 , 48 ]. However, some of these inhibitors could have multiple targets, such as BM212 that binds both MmpL3 and the transcriptional regulator of ethionamide EthR2 [ 49 ].…”

Section: Resultsmentioning

confidence: 99%

A Hydrazine–Hydrazone Adamantine Compound Shows Antimycobacterial Activity and Is a Probable Inhibitor of MmpL3

Briffotaux

Huang

et al. 2022

Molecules

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Tuberculosis remains an important cause of morbidity and mortality throughout the world. Notably, an important number of multi drug resistant cases is an increasing concern. This problem points to an urgent need for novel compounds with antimycobacterial properties and to improve existing therapies. Whole-cell-based screening for compounds with activity against Mycobacterium tuberculosis complex strains in the presence of linezolid was performed in this study. A set of 15 bioactive compounds with antimycobacterial activity in vitro were identified with a minimal inhibitory concentration of less than 2 µg/mL. Among them, compound 1 is a small molecule with a chemical structure consisting of an adamantane moiety and a hydrazide–hydrazone moiety. Whole genome sequencing of spontaneous mutants resistant to the compounds suggested compound 1 to be a new inhibitor of MmpL3. This compound binds to the same pocket as other already published MmpL3 inhibitors, without disturbing the proton motive force of M. bovis BCG and M. smegmatis. Compound 1 showed a strong activity against a panel ofclinical strains of M. tuberculosis in vitro. This compound showed no toxicity against mammalian cells and protected Galleria mellonella larvae against M. bovis BCG infection. These results suggest that compound 1 is a promising anti-TB agent with the potential to improve TB treatment in combination with standard TB therapies.

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Section: Resultsmentioning

confidence: 99%

A Hydrazine–Hydrazone Adamantine Compound Shows Antimycobacterial Activity and Is a Probable Inhibitor of MmpL3

Briffotaux

Huang

et al. 2022

Molecules

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“…Trehalose is a sugar widely distributed in bacteria, fungi, and other higher organisms, playing different biological functions. In some plant bacterial pathogens, it plays a important role in enhancing colonization and enhancing virulence ( 34 , 35 ).The trehalose-monomycolate is a precursor for the synthesis of mycolic acid essential for the synthesis of the bacterial cell wall and is pathogenic ( 36 ). Capsule plays the most critical role of P. multocida serotype A, which is a critical structural component and a virulence factor ( 37 ).…”

Section: Discussionmentioning

confidence: 99%

Genomic and Transcriptomic Analysis of Bovine Pasteurella multocida Serogroup A Strain Reveals Insights Into Virulence Attenuation

et al. 2021

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Pasteurella multocida is one of the primary pathogens of bovine respiratory disease (BRD), and causes huge losses in the cattle industry. The Pm3 strain was a natural isolate, which is a strong form of pathogen and is sensitive to fluoroquinolones antibiotics. A high fluoroquinolone resistant strain, Pm64 (MIC = 64 μg/mL), was formed after continuous induction with subinhibitory concentration (1/2 MIC) of enrofloxacin, with the enhanced growth characteristics and large attenuation of pathogenicity in mice. This study reports the whole genome sequence and the transcription profile by RNA-Seq of strain Pm3/Pm64. The results showed an ineffective difference between the two strains at the genome level. However, 32 genes could be recognized in the gene islands (GIs) of Pm64, in which 24 genes were added and 8 genes were lost. Those genes are involved in DNA binding, trehalose metabolism, material transportation, capsule synthesis, prophage, amino acid metabolism, and other functions. In Pm3 strain, 558 up-regulated and 568 down-regulated genes were found compared to Pm64 strain, from which 20 virulence factor-related differentially expressed genes (DEGs) were screened. Mainly differentially transcribed genes were associated with capsular polysaccharide (CPS), lipopolysaccharide (LPS), lipooligosaccharide (LOS). Iron utilization, and biofilm composition. We speculated that the main mechanism of virulence attenuation after the formation of resistance of Pm64 comes from the change of the expression profile of these genes. This report elucidated the toxicity targets of P. multocida serogroup A which provide fundamental information toward the understanding of the pathogenic mechanism and to decreasing antimicrobial drugs resistance.

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“…The TDM makes the covalent bond with the arabinogalactan polysaccharides to synthesize a packed and MA-based hydrophobic outer cell wall of Mtb (Figure 1). The MA-based hydrophobic outer cell wall of Mtb is impermeable to many chemical compounds, including antibiotics, and protects and contributes to the pathogenic success of Mtb [14,16]. Therefore, the expression of MmpL3 is essential for Mtb's survival and pathogenicity [14][15][16][17][18][19].…”

Section: Mycobacterial Membrane Protein Large 3 (Mmpl3)mentioning

confidence: 99%

“…Therefore, the expression of MmpL3 is essential for Mtb's survival and pathogenicity [14][15][16][17][18][19]. The inhibitors of MmpL3 (SQ109) cause the diminution of MmpL3, which leads to the cessation of cell wall synthesis, cell division, and thevrapid death of Mtb [14][15][16][17][18][19]. The MA-based hydrophobic outer cell wall of Mtb is impermeable to many chemical compounds, including antibiotics, and protects and contributes to the pathogenic success of Mtb [14,16].…”

Section: Mycobacterial Membrane Protein Large 3 (Mmpl3)mentioning

confidence: 99%

MmpL3 Inhibition as a Promising Approach to Develop Novel Therapies against Tuberculosis: A Spotlight on SQ109, Clinical Studies, and Patents Literature

et al. 2022

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Tuberculosis (TB) is accountable for considerable global morbidity and mortality. Effective TB therapy with multiple drugs completes in about six months. The longer duration of TB therapy challenges patient compliance and contributes to treatment collapse and drug resistance (DR) progress. Therefore, new medications with an innovative mechanism of action are desperately required to shorten the TB therapy’s duration and effective TB control. The mycobacterial membrane protein Large 3 (MmpL3) is a novel, mycobacteria-conserved and recognized promiscuous drug target used in the development of better treatments for multi-drug resistance TB (MDR-TB) and extensively drug-resistant TB (XDR-TB). This article spotlights MmpL3, the clinical studies of its inhibitor (SQ109), and the patent literature. The literature on MmpL3 inhibitors was searched on PubMed and freely available patent databases (Espacenet, USPTO, and PatentScope). SQ109, an analog of ethambutol (EMB), is an established MmpL3 inhibitor and has completed Phase 2b-3 clinical trials. Infectex and Sequella are developing orally active SQ109 in partnership to treat MDR pulmonary TB. SQ109 has demonstrated activity against drug-sensitive (DS) and drug-resistant (DR) Mycobacterium tuberculosis (Mtb) and a synergistic effect with isoniazid (INH), rifampicin (RIF), clofazimine (CFZ), and bedaquiline (BNQ). The combination of SQ109, clofazimine, bedaquiline, and pyrazinamide (PZA) has been patented due to its excellent anti-TB activity against MDR-TB, XDR-TB, and latent-TB. The combinations of SQ109 with other anti-TB drugs (chloroquine, hydroxychloroquine, and sutezolid) have also been claimed in the patent literature. SQ109 is more potent than EMB and could substitute EMB in the intensive stage of TB treatment with the three- or four-drug combination. Developing MmpL3 inhibitors is a promising approach to fighting the challenges associated with DS-TB and DR-TB. The authors foresee MmpL3 inhibitors such as SQ109 as future drugs for TB treatment.

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Mycobacterial Membrane Protein Large 3 (MmpL3) Inhibitors: A Promising Approach to Combat Tuberculosis

Cited by 33 publications

References 57 publications

A Hydrazine–Hydrazone Adamantine Compound Shows Antimycobacterial Activity and Is a Probable Inhibitor of MmpL3

A Hydrazine–Hydrazone Adamantine Compound Shows Antimycobacterial Activity and Is a Probable Inhibitor of MmpL3

Genomic and Transcriptomic Analysis of Bovine Pasteurella multocida Serogroup A Strain Reveals Insights Into Virulence Attenuation

MmpL3 Inhibition as a Promising Approach to Develop Novel Therapies against Tuberculosis: A Spotlight on SQ109, Clinical Studies, and Patents Literature

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