Bottlenecks and opportunities in antibiotic discovery against Mycobacterium tuberculosis

Craggs, Peter D.; Carvalho, Luiz Pedro S. de

doi:10.1016/j.mib.2022.102191

Cited by 11 publications

(12 citation statements)

References 65 publications

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“…It is commonly accepted that one of the key causes for this resiliency is the Mycobacterium tuberculosis cell envelope [ 6 , 7 ]. Atypical among bacteria, it has an elaborate dense multilayered structure, devoid of the majority of transporters, that helps to protect it against the actions of the host immune cells, adverse environments, and many antimicrobial agents.…”

Section: Introductionmentioning

confidence: 99%

Conformational Dynamics and Stability of Bilayers Formed by Mycolic Acids from the Mycobacterium tuberculosis Outer Membrane

et al. 2023

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Bilayers of mycolic acids (MAs) form the outer membrane of Mycobacterium tuberculosis that has high strength and extremely low permeability for external molecules (including antibiotics). For the first time, we were able to study them using the all-atom long-term molecular dynamic simulations (from 300 ns up to 1.2 μs) in order to investigate the conformational changes and most favorable structures of the mycobacterial membranes. The structure and properties of the membranes are crucially dependent on the initial packing of the α-mycolic acid (AMA) molecules, as well as on the presence of the secondary membrane components, keto- and methoxy mycolic acids (KMAs and MMAs). In the case of AMA-based membranes, the most labile conformation is W while other types of conformations (sU as well as sZ, eU, and eZ) are much more stable. In the multicomponent membranes, the presence of the KMA and MMA components (in the W conformation) additionally stabilizes both the W and eU conformations of AMA. The membrane in which AMA prevails in the eU conformation is much thicker and, at the same time, much denser. Such a packing of the MA molecules promotes the formation of a significantly stronger outer mycobacterial membrane that should be much more resistant to the threatening external factors.

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Section: Introductionmentioning

confidence: 99%

Conformational Dynamics and Stability of Bilayers Formed by Mycolic Acids from the Mycobacterium tuberculosis Outer Membrane

et al. 2023

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“…Nevertheless, the anti-tubercular drug discovery and development projects face many complications that result in high attrition rates, leaving clinical needs unmet [ 47 , 48 , 49 ]. In particular, the target-based approaches using biochemical screening assays and/or in silico models [ 50 ] to identify and optimize inhibitors have so far failed to produce any clinical drug candidates, primarily due to their lack of whole-cell activity [ 30 , 48 ].…”

Section: Introductionmentioning

confidence: 99%

“…In particular, the target-based approaches using biochemical screening assays and/or in silico models [ 50 ] to identify and optimize inhibitors have so far failed to produce any clinical drug candidates, primarily due to their lack of whole-cell activity [ 30 , 48 ]. It is commonly accepted that one of the key causes for this is the extremely low permeability of the mycobacterial cell envelope [ 49 ]. Atypical among bacteria, the M. tuberculosis cell envelope has an elaborate dense multilayered structure devoid of the majority of transporters, with the wax-like outer membrane formed by mycolic acids and their derivatives [ 12 , 49 ].…”

Section: Introductionmentioning

confidence: 99%

“…It is commonly accepted that one of the key causes for this is the extremely low permeability of the mycobacterial cell envelope [ 49 ]. Atypical among bacteria, the M. tuberculosis cell envelope has an elaborate dense multilayered structure devoid of the majority of transporters, with the wax-like outer membrane formed by mycolic acids and their derivatives [ 12 , 49 ]. Its penetration is believed to be facilitated by the relatively higher lipophilicity of anti-TB drugs (compared to other antibacterials), requiring reassessment of the standard drug-likeness rules [ 38 , 49 , 51 ] and the shift of the overall ADME analysis towards the local (microenvironment-based) drug exposure [ 52 ].…”

Section: Introductionmentioning

confidence: 99%

“…Atypical among bacteria, the M. tuberculosis cell envelope has an elaborate dense multilayered structure devoid of the majority of transporters, with the wax-like outer membrane formed by mycolic acids and their derivatives [ 12 , 49 ]. Its penetration is believed to be facilitated by the relatively higher lipophilicity of anti-TB drugs (compared to other antibacterials), requiring reassessment of the standard drug-likeness rules [ 38 , 49 , 51 ] and the shift of the overall ADME analysis towards the local (microenvironment-based) drug exposure [ 52 ]. Although the whole-cell phenotypic screening followed by target elucidation is presently seen as the most efficient approach to the tuberculosis drug discovery [ 30 , 48 ], the ability to predict and optimize envelope permeability for a potential drug using in silico models would be very valuable in any pipeline.…”

Section: Introductionmentioning

confidence: 99%

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Machine Learning Prediction of Mycobacterial Cell Wall Permeability of Drugs and Drug-like Compounds

et al. 2023

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The cell wall of Mycobacterium tuberculosis and related organisms has a very complex and unusual organization that makes it much less permeable to nutrients and antibiotics, leading to the low activity of many potential antimycobacterial drugs against whole-cell mycobacteria compared to their isolated molecular biotargets. The ability to predict and optimize the cell wall permeability could greatly enhance the development of novel antitubercular agents. Using an extensive structure–permeability dataset for organic compounds derived from published experimental big data (5371 compounds including 2671 penetrating and 2700 non-penetrating compounds), we have created a predictive classification model based on fragmental descriptors and an artificial neural network of a novel architecture that provides better accuracy (cross-validated balanced accuracy 0.768, sensitivity 0.768, specificity 0.769, area under ROC curve 0.911) and applicability domain compared with the previously published results.

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Membrane-active and DNA binding related double-action antimycobacterial mechanism of antimicrobial peptide W3R6 and its synthetic analogs

Wang

Feng

et al. 2023

Biochimica et Biophysica Acta (BBA) - General Subjects

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Bottlenecks and opportunities in antibiotic discovery against Mycobacterium tuberculosis

Cited by 11 publications

References 65 publications

Conformational Dynamics and Stability of Bilayers Formed by Mycolic Acids from the Mycobacterium tuberculosis Outer Membrane

Conformational Dynamics and Stability of Bilayers Formed by Mycolic Acids from the Mycobacterium tuberculosis Outer Membrane

Machine Learning Prediction of Mycobacterial Cell Wall Permeability of Drugs and Drug-like Compounds

Membrane-active and DNA binding related double-action antimycobacterial mechanism of antimicrobial peptide W3R6 and its synthetic analogs

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