Neoteric advancement in TB drugs and an overview on the anti-tubercular role of peptides through computational approaches

Khusro, Ameer; Aarti, Chirom; Barbabosa‐Pliego, Alberto; Salem, Abdelfattah Z.M.

doi:10.1016/j.micpath.2017.11.034

Cited by 27 publications

(13 citation statements)

References 63 publications

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“…Usually, small molecule compounds or peptides are selected to increase toxin activity because they act as inhibitors of TA interactions. Peptides obtained from various sources have already been investigated for their ability to act as antibacterial agents and to replace existing antibiotics [84,85]. In most cases, toxins do not exhibit toxicity when they are part of a TA complex because the antitoxin completely blocks the active site of the toxin.…”

Section: Application Of Antimicrobial Peptides Based On the Type Imentioning

confidence: 99%

A Systematic Overview of Type II and III Toxin-Antitoxin Systems with a Focus on Druggability

Kang

Kim

Jin

et al. 2018

Toxins

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Toxin-antitoxin (TA) systems are known to play various roles in physiological processes, such as gene regulation, growth arrest and survival, in bacteria exposed to environmental stress. Type II TA systems comprise natural complexes consisting of protein toxins and antitoxins. Each toxin and antitoxin participates in distinct regulatory mechanisms depending on the type of TA system. Recently, peptides designed by mimicking the interfaces between TA complexes showed its potential to activate the activity of toxin by competing its binding counterparts. Type II TA systems occur more often in pathogenic bacteria than in their nonpathogenic kin. Therefore, they can be possible drug targets, because of their high abundance in some pathogenic bacteria, such as Mycobacterium tuberculosis. In addition, recent bioinformatic analyses have shown that type III TA systems are highly abundant in the intestinal microbiota, and recent clinical studies have shown that the intestinal microbiota is linked to inflammatory diseases, obesity and even several types of cancer. We therefore focused on exploring the putative relationship between intestinal microbiota-related human diseases and type III TA systems. In this paper, we review and discuss the development of possible druggable materials based on the mechanism of type II and type III TA system.

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Section: Application Of Antimicrobial Peptides Based On the Type Imentioning

confidence: 99%

A Systematic Overview of Type II and III Toxin-Antitoxin Systems with a Focus on Druggability

Kang

Kim

Jin

et al. 2018

Toxins

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“…One of the most influential characteristics of peptides is their pleiotropic effects towards a wide range of biological targets, thus making them better drug candidates with lower toxicity than that of small molecules. Several studies have shown the anti-tubercular properties of peptides and their unique mechanism of actions, suggesting that they are an ideal approach for TB management [5]. Peptides derived from human immune and non-immune cells, venom, fungi, bacteria, and several other sources have been shown to act as effective anti-tubercular agents [3].…”

Section: Introductionmentioning

confidence: 99%

“…However, the experimental identification and development of AtbPs is time-consuming and expensive. To assist and expedite the discovery of AtbPs, in silico methods are needed prior to their synthesis [5]. A trending computational method, machine learning (ML), could provide an excellent platform for the prediction and design of AtbPs.…”

Section: Introductionmentioning

confidence: 99%

AtbPpred: A Robust Sequence-Based Prediction of Anti-Tubercular Peptides Using Extremely Randomized Trees

Manavalan

Basith

Shin

et al. 2019

Computational and Structural Biotechnology Journal

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Mycobacterium tuberculosis is one of the most dangerous pathogens in humans. It acts as an etiological agent of tuberculosis (TB), infecting almost one-third of the world's population. Owing to the high incidence of multidrug-resistant TB and extensively drug-resistant TB, there is an urgent need for novel and effective alternative therapies. Peptide-based therapy has several advantages, such as diverse mechanisms of action, low immunogenicity, and selective affinity to bacterial cell envelopes. However, the identification of anti-tubercular peptides (AtbPs) via experimentation is laborious and expensive; hence, the development of an efficient computational method is necessary for the prediction of AtbPs prior to both in vitro and in vivo experiments. To this end, we developed a two-layer machine learning (ML)-based predictor called AtbPpred for the identification of AtbPs. In the first layer, we applied a two-step feature selection procedure and identified the optimal feature set individually for nine different feature encodings, whose corresponding models were developed using extremely randomized tree (ERT). In the second-layer, the predicted probability of AtbPs from the above nine models were considered as input features to ERT and developed the final predictor. AtbPpred respectively achieved average accuracies of 88.3% and 87.3% during cross-validation and an independent evaluation, which were ~8.7% and 10.0% higher than the state-of-the-art method. Furthermore, we established a user-friendly webserver which is currently available at http://thegleelab.org/AtbPpred . We anticipate that this predictor could be useful in the high-throughput prediction of AtbPs and also provide mechanistic insights into its functions.

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“…TB can infect any part of the body although disease manifestation is generally observed in the lungs. Apart from pulmonary TB, extra-pulmonary TB is mainly found in immunocompromised individuals which includes osseous tuberculosis found in the bones and tuberculous ulcer occurring on the skin 8 .…”

Section: Tb Etiology and Global Tb Crisismentioning

confidence: 99%

“…The innermost layer is a typical phospholipid bilayer plasma membrane (PM), then a peptidoglycan (PG) layer provides a sacculus support to the plasma membrane and it is linked externally to a layer of arabinoglactan (AG). Via the mycoloyl residues (mycolic acids), this covalent PG-AG complex is linked to the outer membrane Synthesis of cell wall is mediated by the mycolyl transferases, namely the antigen-85 protein complexes 8 . These transferases catalyse the transfer of mycolic acid in the cytosolic compartment from TMM to form TDM and a free trehalose.…”

Section: Mycobacterial Cell Envelopementioning

confidence: 99%

Novel D-LAK peptides combinations against mycobacteria : bioefficacy and mechanistic studies

Dede¹

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Emergence of multidrug-resistant tuberculosis (MDR-TB) renders the two most powerful and commonly used TB antibiotics, rifampicin and isoniazid, ineffective. There is an urgent need for the development of safe and effective strategies against drug-resistant TB. Based on previous studies, two novel antimicrobial peptides, namely D-LAK120-A and D-LAK120-HP13, both consist entirely of D-amino acid residues, have demonstrated inhibitory effect on MDR Mycobacterium tuberculosis (Mtb) strains when cultured in macrophages and potentiated the antimycobacterial activity of isoniazid in vitro. Here, the antimycobacterial activity of D-LAK peptides in combination with anti-TB drugs against MDR-TB clinical isolates was investigated. Furthermore, the mechanisms of action of the proline-containing and proline-free D-LAK peptides, anti-TB drugs alone or in combinations were studied using two mycobacterial models Mycobacterium smegmatis and the severely attenuated Mtb Bleupan. Finally, the applicability of these two microorganisms for mycobacterial studies was discussed. In vitro and ex vivo antimycobacterial assays revealed the synergy between D-LAK peptides and rifampicin or isoniazid against MDR Mtb strain. These findings suggested D-LAK peptide can facilitate the re-sensitization of MDR-TB clinical isolates towards rifampicin and isoniazid possibly through their surface activity. To gain further understanding on their mechanisms on mycobacteria, M. smegmatis was employed due to its fast-growing nature and widespread usage in TB studies. With confocal and transmission electron microscopy, the surface-active action of D-LAK peptides were observed which led to visible morphological changes in M. smegmatis. Using high-resolution magic angle spinning (HR-MAS) nuclear magnetic resonance (NMR) metabolomics, trans-1,6-diphenyl-1,3,5hexatriene (DPH) and Laurdan fluorescence spectroscopy, it was shown that bacterial iv metabolism was substantially altered when challenged with anti-TB agents, specifically by the remodelling of mycobacterial membrane. The proline-containing D-LAK120-HP13 and proline-free D-LAK120-A peptides demonstrated disparate behaviours in the initiation of membrane remodelling which provides possible rationale for their synergistic interaction with anti-TB agents. These techniques were then applied to the study of another potential mycobacterial model Mtb Bleupan which was selected for its safer nature as a Mtb surrogate. Changes in membrane components triggered by anti-TB agents were observed but the effect was subtler than that observed in M. smegmatis. These findings suggested the potential of using these biophysical techniques to study the action of anti-TB drugs on mycobacteria and to elucidate the underlying mechanism of synergy demonstrated in the combinations of D-LAK peptides with anti-TB agents. Finally, the applicability of M. smegmatis and Mtb Bleupan to be exploited as a Mtb surrogate was evaluated. Some key differences in response to anti-TB agents were detected between Mtb Bleupan and M. smegmatis in...

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Neoteric advancement in TB drugs and an overview on the anti-tubercular role of peptides through computational approaches

Cited by 27 publications

References 63 publications

A Systematic Overview of Type II and III Toxin-Antitoxin Systems with a Focus on Druggability

A Systematic Overview of Type II and III Toxin-Antitoxin Systems with a Focus on Druggability

AtbPpred: A Robust Sequence-Based Prediction of Anti-Tubercular Peptides Using Extremely Randomized Trees

Novel D-LAK peptides combinations against mycobacteria : bioefficacy and mechanistic studies

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