Description
Mycobacterium tuberculosis (Mtb) is one of the deadliest diseases. While antibiotics exist to treat it, their efficacy has waned in recent years due to drug-resistant strains of the bacteria. While there are methods to detect drug resistance in Mtb, there are potentially mutations which the bacteria harbor that could explain multiple resistances simultaneously, as well as explain novel mechanisms of drug resistance. Towards the identification of multiple and novel drug resistance mutations in Mtb, we analyzed the results of whole genome sequencing for 5,958 Mtb isolates using a three-part approach. We used the protein-protein interaction network for Mtb in the STRING database to identify mutant proteins which were incident to two, or once removed from being incident to two proteins from an original protein set known to cause drug resistance in the bacteria in part one. In the second part, the set of starting proteins was changed to include any two mutated proteins between two isolates with unknown drug resistance to a certain antibiotic. In the last part, the entire network was clustered using an algorithm SPICi, and the most mutated clusters in unknown resistance isolates were determined and functionally characterized using Gene Ontology terms. The proteins which most commonly appeared between double-resistant isolates were GrcC2, associated with isoprenoid biosynthesis in aminoglycoside and pyrazinamide resistance. Mutations in proteins associated with ESX secretion systems were found to correlate to fluoroquinolone single resistance. When using a set of all mutated proteins between two drug resistant isolates, many hypothetical genes were identified as potentially important, however they normally have ill-defined functional roles. The most mutated cluster in drug resistant isolates included PE_PGRS49 and PE_PGRS50, both part of a grouping of proteins in Mtb called PE/PPE proteins which also have murky functional annotation. The other most represented clusters were heavy in lipid metabolism, and also vitamin metabolism, which could be an interesting initiating point for future studies. Overall, the results of this study were exploratory, with mostly poor correlation and low sensitivity and specificity. If experimentally validated, the multiple and novel mechanisms of drug resistance identified herein may be corroborated.
