AI-Enabled Parabolic Response Surface Approach Identifies Ultra Short-Course Near-Universal TB Drug Regimens

Tuberculosis (TB) is a major health problem that causes more deaths worldwide than any other single infectious disease. Current multidrug therapy for tuberculosis is exceedingly lengthy, leading to poor drug adherence, and consequently the emergence of drug resistance. Hence, much more rapid treatments are needed. Experimentally identifying the most synergistic drug combinations among available drugs is complicated by the astronomical number of possible drug-dose combinations. This problem is dealt with by the use of an artificial-intelligence-enabled parabolic response surface platform in conjunction with an in vitro Mycobacterium tuberculosis–infected macrophage cell culture assay amenable to high-throughput screening. This strategy allows rapid identification of the most effective drug-dose combinations by testing only a small fraction of the total drug-dose efficacy response surface. The same platform is then used to optimize the in vivo doses of each drug in the most potent regimens. Thus, regimens are identified that are dramatically more effective than the Standard Regimen in treating TB in a mouse model—a model broadly predictive of drug efficacy in humans. The most effective regimens reported herein shorten the duration of treatment required to achieve relapse-free cure by 80% and are suitable for treating both drug-sensitive and most drug-resistant cases of tuberculosis.