## 2 Which New Drugs and Regimens? First, further progress would require improving molecules of known classes. The Nix-TB trial has raised much hope for the development of a short fully oral regimen for the treatment of severe drug-resistant TB. The use of the tested regimen may, however, be limited in clinical practice due to severe side-effects caused by linezold. While a trial is on-going to test lower dose of linezold, [14] new oxazolidinones are being developed to try and reduce toxic effects. Four oxazolidinones are now in early phases of the clinical development pipeline, i.e., contezolid, delpazolid, sutezolid and TBI-223 [7]. Similarly, the use of clofazimine, another important component of the therapeutic armamentarium against drug-resistant TB, is hampered by potential undesirable skin pigmentation. Novel riminophenazine derivatives are being developed with the goal of maintaining potent anti-tuberculosis activity while lowering side effects-such as TBI-166, a compound currently in clinical development in China [15]. The second requirement is that of developing new agents or, better classes of anti-TB drugs. While improving existing classes has the advantage of initiating the risky discovery process with a well-characterized, validated compound, some level fast adaptation of bacterial populations can be expected. Ideally, therefore, research and development should produce entirely new classes, targets and modes of action to avoid cross-resistance to existing antibiotics. Thus, in parallel with improvements in existing drug and regimen models, innovative approaches, including discovery of novel chemical scaffolds and identification of new targets, are urgently needed. The discovery of bedaquiline opened the way to investigating the possibility to alter the energy metabolism in mycobacteria, in particular the oxidative phosphorylation pathway, as a novel target pathway in drug discovery, leading to the depletion of ATP synthesis of _M. tuberculosis_. New classes of antibacterial drugs interfering with elements of this pathway have been shown to be highly active in combating latent mycobacterial infections. The discovery of Q203, a candidate drug targeting the cytochrome bc1 complex in the respiratory chain, has highlighted the importance of this new target pathway. Inhibiting the bacterial energy metabolism might be a key feature of novel and sterilizing drug combinations for the treatment of TB [16]. Furthermore, Q203 was shown to have good synergy with bedaquiline in the murine chronic infection model, indicating promising potential for new treatment regimens [17]. Thus, the combination of drugs targeting various elements of the oxidative phosphorylation pathway could lead to a completely new regimen for drug-susceptible and multi-drug resistant tuberculosis. A series of new compounds are currently developed that focus on newly identified targets. Four of these inhibit DprE1 (decaprenylphosphoryl-\(\beta\)-D-ribose 2-epimerase), a flavoenzyme that catalyses a key step in the synthesis of the complex cell wall of _M. tuberculosis_: macozinone, BTZ-043, OPC-167832 and TBA-7371 [7]. Another compound targets the leucyl-tRNA synthetase (LeuRS), which is essential for protein synthesis (GSK3036656). The third approach is to identify efficient and seamless development processes to accelerate testing of novel treatment regimens. The current TB treatment development pathway is complex, lengthy and costly, partly due to the fact that some drugs are still being developed individually, and partly due to the lack of reliable surrogate markers of treatment outcomes and the lack of predictive quantitative relationships between Phase II and Phase III outcomes [18].