This invention presents a novel series of modified cephalosporins, which exclusively target non-replicating mycobacterium tuberculosis.
Tuberculosis (TB) is a chronic disease primarily affecting the lungs caused by Mycobacterium tuberculosis (MTB) and is presently one of the deadliest infectious disease worldwide. Despite the availability of effective chemotherapy, more than 8.6 million cases of active disease and 1.4 million deaths were reported in 2012. One of the major challenges of treating MTB is bacterial persistence, which occurs when the bacteria enter a dormant, non-replicating state and create attack-resistant colonies called biofilms, which contain a high proportion of non-replicating MTB and are less susceptible to existing drugs. The slow growth and dormancy of MTB contributes to the chronic nature of the infection, and effective treatment of active disease requires lengthy multidrug regimens (up to 24 months), which are associated with severe side effects with only 30-50% positive treatment outcomes. Prolonged treatment and poor adherence to therapy also increase the emergence of multidrug-resistant (MDR) strains. Therefore, new treatments are urgently needed to shorten the duration of the standard treatment, target non-replicating strains of MTB, and prevent the emergence of MDR. Ideal treatment of TB includes a combination of drugs, which can kill replicating and non-replicating strains.
These compounds are beneficial for the treatment of dormant, non-replicating strains of Mycobacterium tuberculosis.
The two main classes of cephalosporins synthesized bear an ester or alternatively an oxadiazole isostere at C-2 of the cephalosporin ring system (a position that is almost exclusively a carboxylic acid in clinically used agents in the class).
Two modified cephalosporin compounds have been identified which are exclusively active against non-replicating strains of MTB. Along with their stability in human plasma (under a wide range of pH values), solubility, and membrane permeability, these compounds are uniquely able to target intracellular MTB residing in macrophages without toxicity to macrophages or other mammalian cells.
These cephalosporin derivatives exclusively target non-replicating MTB with insensitivity to a wide spectrum of bacterial strains and are uniquely able to target intracellular MTB residing in macrophages, an important site of initial infection (within alveolar macrophages) without toxicity to macrophages or other mammalian cells.
This technology can be used to identify mechanisms of dromancy or multi-drug resisance in non-replicating strains and can potentially be used in combination with other agents active against replicating TB strains.