Selection of Multi-Drug Targets against Drug-Resistant <i>Mycobacterium tuberculosis</i> XDR1219 Using the Hyperbolic Mapping of the Protein Interaction Network
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 <i>Mycobacterium tuberculosis</i> protein interaction network (m...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-09-01
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| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/24/18/14050 |
| Summary: | 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 <i>Mycobacterium tuberculosis</i> 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 <i>rpsA</i> and <i>rpsL</i> 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 <i>dprE1</i> and <i>dnaK</i> proteins, which interact with two close DT pairs: arabinosyltransferases (<i>embC</i> and <i>embB</i>), Ser/Thr protein kinase (<i>pknB</i>) and RNA polymerase (<i>rpoB</i>), 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. |
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| ISSN: | 1661-6596 1422-0067 |