Novel Tuberculostatic Agents Suitable for Treatment of Mycobacterium tuberculosis Infections of the Central Nervous System

Ronald Bartzatt

doi:10.9734/bjpr/2014/10353

Abstract

Aims: To demonstrate the efficacy of five small molecule compounds for inhibiting the growth of Mycobacterium tuberculosis. To present evidence that these compounds will penetrate into the central nervous system.Study Design: Five small molecule compounds bearing a hydrazide group were synthesized utilizing microwave excitation. These compounds were then placed into tissue culture with Mycobacterium tuberculosis at various concentrations for evaluation of bacterial growth inhibition.Place and Duration of Study: The compounds to be tested were prepared at the University of Nebraska Chemistry Department August 2013. The evaluation of antibacterial activity was determined at the Texas A&M Health Science Center during October to December of 2013.Methodology: Applying microwave excitation for generation of hydrazide groups within the structure of small molecule carboxylic acids, five agents were prepared for evaluation of bacterial growth inhibition. These agents were dissolved into tissue culture media at various concentrations. Having various levels of tuberculostatic agents, then tuberculosis bacteria were added to determine level of growth inhibition. Growth inhibition of the bacteria was achieved and measured by compound concentration for comparison and evaluation.Results: Five compounds having a hydrazide functional group greatly inhibited the growth of Mycobacterium tuberculosis. All five agents had molecular weight less than 215 grams/mole and polar surface area of less than 70 Angstroms2. Values of Log P ranged from -0.226 to 0.998. Values of Log BB (Log [Cbrain/Cblood]) ranged from -0.711 to - 0.525, with a range in central nervous system penetration Cbrain/Cblood of 0.195 to 0.299. All compounds showed zero violations of the Rule of 5. Substantial inhibition of bacterial growth was observed at concentrations as low as 30 micrograms/mL, as measured by optical density and colony forming units.Conclusion: These five hydrazide compounds substantially decreased the proliferation of tuberculosis bacteria at concentrations as low as 30 micrograms/mL. In addition, their physicochemical properties are shown to allow high levels of penetration into the central nervous system.

Highlights

The causative agent for the disease referred to as tuberculosis (TB) is Mycobacterium tuberculosis
The morbidity and mortality of tuberculosis infection of the central nervous system (CNS) presents unique problems even in diagnosis, in addition to clinical treatment due to the difficulty of drugs to penetrate through the blood-brain barrier
For all five compounds and by all methods of measurement, very substantial to complete inhibition of bacteria growth was achieved at concentrations greater than 30 micrograms/mL

Summary

Introduction

The causative agent for the disease referred to as tuberculosis (TB) is Mycobacterium tuberculosis. Infections due to M. tuberculosis are still regarded as a major world-wide health problem. Some estimates place the number of infections at approximately one-third of the entire world’s population [1]. The World Health Organization estimates that by the year 2015 there will be as many as one billion newly infected people and as many as 200 million will develop the active disease [1]. 2 million deaths per year are attributed to TB and each year there can be as many as 9 million new cases [1]. As of the year 2013, it is believed that as much as 95% of new cases and 98% of deaths attributed to TB occur in low-income and middle-income countries [1]. The decay of health services, social-economic decline, and emergence of drug-resistant forms of TB contribute the most to these alarming trends [1]

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Conclusion