Deforestation is one of the most pressing environmental issues that the world is facing currently. It is the conversion of forested land to non-forested land by humans. Deforestation occurs when a land dominated by naturally occurring trees is converted to provide certain services in response to the human demand. The indiscriminate felling of trees has resulted in a reduction of 3.16% in the global forest cover from 1990 to 2015. Although India has seen an increment in the total forest cover of ca. 1%, still there are certain regions in the country that have sought a decrease in the forest cover. The main reasons attributed to the reduction in forest cover are shifting cultivation, rotational felling, other biotic pressures, diversion of forest lands for developmental activities, etc. Continuous illicit cutting of trees has impacted the microclimatic conditions, hydrological cycle, soil quality, biodiversity, etc. of the country, thereby making the country more vulnerable for any uneventful happening. Sustainable forest management practices, alternatives for shifting cultivation, promotion of plantation outside the forest and the usage of certified forest products, etc. are some of the measures that can be adopted to curb the rate of deforestation.
The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis calls for an immediate search for novel treatment strategies. Recently, BlaC, the principal beta-lactamase of Mycobacterium tuberculosis, was recognized as a potential therapeutic target. BlaC belongs to Ambler class A, which is generally susceptible to the beta-lactamase inhibitors currently used in clinics: tazobactam, sulbactam, and clavulanate. Alterations at Ser130 in conserved SDN loop confer resistance to mechanism-based inhibitors (MBIs) commonly observed in various clinical isolates. The absence of clinical evidence of S130G conversion in M. tuberculosis draws our attention to build laboratory mutants of S130G and S130A of BlaC. The study involving steady state, inhibition kinetics, and fluorescence microscopy shows the emergence of resistance against MBIs to the mutants expressing S130G and S130A. To understand the molecular reasoning behind the unavailability of such mutation in real life, we have used circular dichroism (CD) spectroscopy, differential scanning calorimetry (DSC), molecular dynamics (MD) simulation, and stability-based enzyme activity to compare the stability and dynamic behaviors of native and S130G/A mutant form of BlaC. A significant decrease in melting temperature (BlaC TM 60°C, S130A TM 50°C, and S130G TM 45°C), kinetic instability at higher temperature, and comparative dynamic instability correlate the fact that resistance to beta-lactam/beta-lactamase inhibitor combinations will likely not arise from the structural alteration of BlaC, therefore establishing confidence that this therapeutic modality can be potentially applied as a part of a successful treatment regimen against M. tuberculosis.
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