Selection of Multi-Drug Targets against Drug-Resistant Mycobacterium tuberculosis XDR1219 Using the Hyperbolic Mapping of the Protein Interaction Network

Author:

Zahra Noor ul Ain12,Vagiona Aimilia-Christina2,Uddin Reaz1ORCID,Andrade-Navarro Miguel A.2ORCID

Affiliation:

1. Lab 103 PCMD ext., Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan

2. Institute of Organismic and Molecular Evolution, Faculty of Biology, Johannes Gutenberg University, Hans-Dieter-Hüsch-Weg 15, 55128 Mainz, Germany

Abstract

Tuberculosis remains the leading cause of death from a single pathogen. On the other hand, antimicrobial resistance (AMR) makes it increasingly difficult to deal with this disease. We present the hyperbolic embedding of the Mycobacterium tuberculosis protein interaction network (mtbPIN) of resistant strain (MTB XDR1219) to determine the biological relevance of its latent geometry. In this hypermap, proteins with similar interacting partners occupy close positions. An analysis of the hypermap of available drug targets (DTs) and their direct and intermediate interactors was used to identify potentially useful drug combinations and drug targets. We identify rpsA and rpsL as close DTs targeted by different drugs (pyrazinamide and aminoglycosides, respectively) and propose that the combination of these drugs could have a synergistic effect. We also used the hypermap to explain the effects of drugs that affect multiple DTs, for example, forcing the bacteria to deal with multiple stresses like ethambutol, which affects the synthesis of both arabinogalactan and lipoarabinomannan. Our strategy uncovers novel potential DTs, such as dprE1 and dnaK proteins, which interact with two close DT pairs: arabinosyltransferases (embC and embB), Ser/Thr protein kinase (pknB) and RNA polymerase (rpoB), respectively. Our approach provides mechanistic explanations for existing drugs and suggests new DTs. This strategy can also be applied to the study of other resistant strains.

Funder

DAAD

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

Reference77 articles.

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