The present state of the tuberculosis drug development pipeline

Abstract

Tuberculosis now ranks as the leading cause of death in the world due to a single infectious agent. Current standard of care treatment can achieve very high cure rates for drug-sensitive disease but requires a 6-month duration of chemotherapy. Drug-resistant disease requires significantly longer treatment durations with drugs associated with a higher risk of adverse events. Thus, there is a pressing need for a drug regimen that is safer, shorter in duration and superior to current front-line chemotherapy in terms of efficacy. The TB drug pipeline contains several candidates that address one or more of the required attributes of chemotherapeutic regimens that may redefine the standard of care of this disease. Several new drugs have been reported and novel targets have been identified allowing regimens containing new compounds to trickle into clinical studies. Furthermore, a recent paradigm-shift in understanding the pharmacokinetics of anti-tubercular drugs is revolutionizing the way we select compounds for clinical progression.

Figure 1.. Lesion pharmacokinetics of representative anti-TB drugs.

(A) Differences in the physicochemical properties of drugs, coupled with the complex architecture of TB granulomas result in varying permeability profiles across different lesion types. The result is periods of monotherapy that generate selective pressure for emergence of resistance. (B) Imaging MS (top) and H&E (bottom) stained section of necrotic nodules and cavities (outlined in white) in rabbit lungs showing accumulation of rifampicin 6 hrs after the 7^th daily dose. Image in (B) courtesy of Dr. Brendan Prideaux and Dr. Veronique Dartois of New Jersey Medical School, Rutgers, The State University of New Jersey