Predicting Antibiotic Resistance in Mycobacterium tuberculosis

Tuberculosis (TB) is a deadly infectious disease caused by the bacteriumMycobacterium tuberculosis. The emergence and spread of multi-drug resistant (MDR) TB, which is resistant to the first line antibiotics rifampicin and isoniazid, is making treatment and control of the disease more difficult. Fluoroquinolone antibiotics, such as moxifloxacin and levofloxacin, are commonly used as second line antibiotics to treat MDR TB. These drugs target the TB DNA gyrase enzyme and cut mycobacterial DNA which leads to cell death. However, resistance to fluoroquinolones has arisen in multi-drug resistant (MDR) TB. Many cases of fluoroquinolone resistance have been attributed to mutations in the DNA gyrase genes. Although some common resistance causing mutations have been identified in the gyrase genes, the clinical implications of as yet unseen or uncharacterised mutations are not known - this could be of serious detriment to the accurate diagnosis and effective treatment of MDR TB.

The aim of this project is to employ molecular dynamics simulation approaches and free energy calculations to accurately predict which mutations in the DNA gyrase genes can cause resistance to fluoroquinolone antibiotics, and to what extent. The project also aims to help explain why different fluoroquinolones have differing potency when used to treat MDR TB. Whole genome sequencing and phenotypic data collected by the Comprehensive Resistance Prediction for Tuberculosis: an International Consortium (CRyPTIC) project will be used to help validate these predictions.

The work conducted in this project may aid diagnoses of cases of fluoroquinolone resistance in TB and help inform treatment decisions. Furthermore, insights into possible mechanisms of DNA gyrase resistance to fluoroquinolone antibiotics may prove useful in the diagnosis and treatment of other bacterial infections such asStaphylococcus aureus, Klebsiella pneumoniae, Clostridium difficile and many others that require DNA gyrase enzymes for survival. The predictions may also provide direction for the design of new fluoroquinolone antibiotics that will be more effective against MDR bacteria.