Tuberculosis, commonly known as TB, is one of the world’s deadliest killers caused by the bacteria, Mycobacterium tuberculosis. Every day, almost 4000 people lose their lives to TB that takes the data up to 1.5 million deaths per year. However, the positive aspect of the story is, according to estimates by World Health Organization approx. 63 million lives have been saved by the global effort to combat TB since the year 2000. People in low- and middle-income countries are the major sufferers of the crises, including India. Clinical misuse including poor quality medication and inappropriate duration of therapy are some of the factors that cause such a condition. The disease is curable by using a certain regimen of antibiotics for the recommended period. However, misuse of antibiotics has led to the development of antimicrobial resistance among bacterial strains. Hence, at present time, antimicrobial resistance has become a new challenge in the treatment of several infectious diseases including TB. Resistance majorly arises due to the specific alteration/modifications/mutations in the bacterial genome.
Garima Singh and Dr. Yusuf Akhter from Babasaheb Bhimrao Ambedkar University, Lucknow have attempted to elucidate the working of the transporter proteins, which are involved in drug efflux from the bacterial cell. These transporters are causing multi-drug resistance in the bacteria, by effluxing out the antibiotics across the plasma membrane. In general, membrane transporters act as carriers/transporters on the bacterial plasma membrane and provide a channel for the import and export of the molecules in and out of the bacterial cell. They have particularly studied the mechanism of action of such a protein, Rv1634, a multidrug efflux transporter from Mycobacterium tuberculosis.
Based on some already available facts, they have tried to fill the gaps in the overall information, by studying the working mechanism of the protein. Initially, a three-dimensional structure and substrate binding site were predicted for the protein. Followed by detection of potential transport channel passing from cytoplasmic end to periplasmic end. Ciprofloxacin and Norfloxacin, two very well know antibiotics were studied using multiple Molecular dynamics simulations to get better insights into active efflux (pumping out) of the drugs across the cell surface. These drugs particularly belong to fluoroquinolone class of compounds, which is a potent group of drugs that target DNA gyrase and topoisomerase IV, vital enzymes in the DNA replication process.
But in case of efflux pumps mediated drug resistance, the targeted drugs are pumped out of the bacterial cell making them completely inefficient for bacterial morbidity. It was also found in the study that the differential interaction of these drugs with the protein was probably due to the substrate specificity present at the substrate-binding pocket. Furthermore, the characteristic working mechanism of the Major facilitator superfamily proteins was also worked out.
This study could be supportive in the development of novel therapeutic drugs against transporter proteins as a target that is majorly involved in causing the antimicrobial-resistance. We also need better strategies for the development of new therapies which could be potential enough to eradicate TB worldwide. However, the consistent efforts by the administration and the scientific community will surely aid in the treatment advancement against the TB. Additionally, on the ground level, certain awareness programmes about the proper use of antibiotics are the need of the hour for the common people. These combined attempts will someway assist in achieving the goals of “End TB Strategy”, a currently ongoing campaign of World Health Organisation.
Source: Press Release
Original research article is available here: https://onlinelibrary.wiley.com/doi/10.1002/prot.26253