Designing durable anti-tuberculosis regimens: physiological targeting, resistance fitness landscapes, and treatment optimization

This narrative review highlights that tuberculosis (TB) treatment succeeds or fails at the regimen level, rather than based on individual drugs. The central challenge is to sustain effective multidrug pressure across a pathogen population in heterogeneous microenvironments. In drug-susceptible TB, rifampicin-based combinations achieve high cure rates; however, prolonged treatment duration, drug toxicity, and treatment interruptions drive resistance. In drug-resistant TB, newer agents like bedaquiline, nitroimidazoles, and repurposed linezolid enable shorter, all-oral regimens, yet durability depends on preventing resistance while maintaining effective exposure. Here, we review the available information on anti-TB drugs, concentrating on the physiological states of pathogen, resistance fitness landscapes, and regimen-level pharmacodynamics. These concepts are considered as complementary perspectives for understanding treatment response and directing future research. First, we map how drug classes distribute activity across pathogen physiological states, thereby establishing the need for mechanistic complementarity. Second, we conceptualize resistance as a constrained evolutionary outcome shaped by mutation supply and fitness costs, as illustrated by resistance to bedaquiline, pretomanid, and linezolid. Third, we integrate lesion pharmacokinetics and combination-response landscapes to demonstrate how spatial drug gradients and microenvironment-specific interactions can guide regimen prioritisation. These concepts are interpreted with WHO target regimen profiles to identify principles for protecting high-value core drugs as finite global assets.