Crystal Structures of Membrane Transporter MmpL3, an Anti-TB Drug Target

Zhang, Bing; Li, Jun; Yang, Xiaolin; Wu, Lijun; Zhang, Jia; Yang, Yang; Zhao, Yao; Zhang, Lu; Yang, Xiuna; Yang, Xiaobao; Cheng, Xi; Liu, Zhijie; Jiang, Biao; Jiang, Hualiang; Guddat, Luke W.; Yang, Haitao; Rao, Zihe

doi:10.1016/j.cell.2019.01.003

Cited by 197 publications

(392 citation statements)

References 87 publications

(86 reference statements)

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“…The assay used a M . tuberculosis cytochrome bd oxidase deletion mutant cydKO , which is hypersusceptible to compounds such as imidazopyridines that target the QcrB subunit of the qcrCAB‐encoded cytochrome bc1 complex . No MIC shift was observed when the cydKO mutant was tested against all selected N ‐acetylazaaurones (Table ).…”

Section: Resultsmentioning

confidence: 99%

Azaaurones as Potent Antimycobacterial Agents Active against MDR‐ and XDR‐TB

et al. 2019

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Herein we report the screening of a small library of aurones and their isosteric counterparts, azaaurones and N‐acetylazaaurones, against Mycobacterium tuberculosis. Aurones were found to be inactive at 20 μm, whereas azaaurones and N‐acetylazaaurones emerged as the most potent compounds, with nine derivatives displaying MIC99 values ranging from 0.4 to 2.0 μm. In addition, several N‐acetylazaaurones were found to be active against multidrug‐resistant (MDR) and extensively drug‐resistant (XDR) clinical M. tuberculosis isolates. The antimycobacterial mechanism of action of these compounds remains to be determined; however, a preliminary mechanistic study confirmed that they do not inhibit the mycobacterial cytochrome bc1 complex. Additionally, microsomal metabolic stability and metabolite identification studies revealed that N‐acetylazaaurones are deacetylated to their azaaurone counterparts. Overall, these results demonstrate that azaaurones and their N‐acetyl counterparts represent a new entry in the toolbox of chemotypes capable of inhibiting M. tuberculosis growth.

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Section: Resultsmentioning

confidence: 99%

Azaaurones as Potent Antimycobacterial Agents Active against MDR‐ and XDR‐TB

et al. 2019

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“…From Sargocentron spiniferum (Forsskål) (Holocentridae) in the South China Sea (as Benedenia sargocentron ) (Zhang et al 2001). …”

Section: Resultsmentioning

confidence: 99%

“…Zhang et al (2001) described Benedenia sargocentron on Sargocentron spiniferum from the South China Sea. However, Deveney and Whittington (2010) determined that B. sargocentron was a junior synonym of B. hawaiiensis , and proposed keeping B. hawaiiensis as the valid name.…”

Section: Resultsmentioning

confidence: 99%

Monogenea of fishes from the lagoon flats of Palmyra Atoll in the Central Pacific

Vidal‐Martínez¹,

Soler-Jiménez²,

Aguirre-Macedo³

et al. 2017

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A survey of the monogeneans of fishes from the lagoon flats of Palmyra Atoll detected 16 species already reported from the Indo-West Pacific faunal region. A total of 653 individual fish from 44 species were collected from the sand flats bordering the lagoon of the atoll. Eighteen species of fish were infected with monogeneans. The monogenean species recovered were: Benedenia hawaiiensis on Acanthurus xanthopterus, Chaetodon auriga, Chaetodon lunula, Mulloidichthys flavolineatus, Pseudobalistes flavimarginatus and Rhinecanthus aculeatus; Ancyrocephalus ornatus on Arothron hispidus; Euryhaliotrema annulocirrus on Chaetodon auriga and Chaetodon lunula; Euryhaliotrema chrysotaeniae on Lutjanus fulvus; Euryhaliotrema grandis on Chaetodon auriga and Chaetodon lunula; Haliotrema acanthuri on Acanthurus triostegus; Haliotrema aurigae on Chaetodon auriga and Chaetodon lunula; Haliotrema dempsteri on Acanthurus xanthopterus; Haliotrema minutospirale on Mulloidichthys flavolineatus; Haliotrematoides patellacirrus on Lutjanus monostigma; Neohaliotrema bombini on Abudefduf septemfasciatus and Abudefduf sordidus; Acleotrema girellae and Acleotrema parastromatei on Kyphosus cinerascens; Cemocotylella elongata on Caranx ignobilis, Caranx melampygus and Caranx papuensis; Metamicrocotyla macracantha on Crenimugil crenilabris; and Pseudopterinotrema albulae on Albula glossodonta. All these monogenean–host combinations represent new geographical records. The monogenean species composition of the Palmyra Atoll is similar to that of the Hawaiian Islands. However, the number of species recovered was lower compared with other localities within the Indo-West Pacific, perhaps due to the geographical isolation of Palmyra Atoll.

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“…The superimposition of the M. abscessus MmpL3 model onto the M. smegmatis MmpL3 structure showed that the drug binding site formerly described was conserved in the transmembrane domain of the M. abscessus MmpL3 (gold sphere in Figure ). Interestingly, this cavity is in the vicinity of residues previously reported to participate to the proton relay . This binding pocket is composed of two hydrophobic cavities, designated Up‐ and Bottom‐pockets (U and B in Figure c) and comprises also a more polar cavity, designated Middle‐pocket (M in Figure c).…”

Section: Resultsmentioning

confidence: 95%

“…The RMSD calculated on the C α of the template is around 0.4 Å and 96 % of the residues are within the Ramachandran criteria. The superimposition of the M. abscessus MmpL3 model onto the M. smegmatis MmpL3 structure showed that the drug binding site formerly described [33] was conserved in the transmembrane domain of the M. abscessus MmpL3 (gold sphere in Figure 4). Interestingly, this cavity is in the vicinity of residues previously reported to participate to the proton relay.…”

Section: Molecular Modellingmentioning

confidence: 96%

Structure‐Based Design and Synthesis of Piperidinol‐Containing Molecules as New Mycobacterium abscessus Inhibitors

et al. 2020

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Non‐tuberculous mycobacterium (NTM) infections, such as those caused by Mycobacterium abscessus, are increasing globally. Due to their intrinsic drug resistance, M. abscessus pulmonary infections are often difficult to cure using standard chemotherapy. We previously demonstrated that a piperidinol derivative, named PIPD1, is an efficient molecule both against M. abscessus and Mycobacterium tuberculosis, the agent of tuberculosis, by targeting the mycolic acid transporter MmpL3. These results prompted us to design and synthesize a series of piperidinol derivatives and to determine the biological activity against M. abscessus. Structure‐activity relationship (SAR) studies pointed toward specific sites on the scaffold that can tolerate slight modifications. Overall, these results identified FMD‐88 as a new promising active analogue against M. abscessus. Also, we determined the pharmacokinetics properties of PIPD1 and showed that intraperitoneal administration of this compound resulted in promising serum concentration and an elimination half‐life of 3.2 hours.

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Crystal Structures of Membrane Transporter MmpL3, an Anti-TB Drug Target

Cited by 197 publications

References 87 publications

Azaaurones as Potent Antimycobacterial Agents Active against MDR‐ and XDR‐TB

Azaaurones as Potent Antimycobacterial Agents Active against MDR‐ and XDR‐TB

Monogenea of fishes from the lagoon flats of Palmyra Atoll in the Central Pacific

Structure‐Based Design and Synthesis of Piperidinol‐Containing Molecules as New Mycobacterium abscessus Inhibitors

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