*6.4. Combination Therapy: Finding Novel Combinations*

What constitutes an 'ideal' combination? Faster time for sputum conversion, faster cure, tolerability, lower rates of drug resistance, lower relapse rates, combination suitable for treating pulmonary and extrapulmonary TB, and other properties, like compatible with comorbidities, etc. The concept of searching for novel combinations is recent; it was first advocated by the GATB [113] by studying a variety of combinations in humans using EBA. The two recently approved drugs, Bedaquiline and Delamanid, were progressed as add-ons to a cocktail of second-line drugs. Pretomanid, in combination

with Bedaquiline and linezolid, has been approved for the treatment of XDR TB patients for whom there is very limited choice [73].

Another question is, can compounds active on the same target be compatible in the same combination? It is possible if the two inhibitors bind to different sites of the same targets, like in the examples of BTZ, PBTZ, and TBA7371. If the resistant mutants for the individual compounds do not confer cross-resistance, can such an approach bring additional advantage to the treatment? This can be relevant in the context of the so-called 'promiscuous targets' in TB and the diverse chemical inhibitors of these targets reported in recent years, e.g., benzothiazinones, azaindoles, and Q 203.
