## 1 Which New Tools Are Necessary to End the Tuberculosis (TB) Epidemic? First of all, achieving the End TB targets will require improved tests for early and rapid detection of TB and for universal drug-susceptibility testing (DST) to reach more patients when they first seek care so that one can cut transmission early and accelerate the decline in TB incidence and mortality. Diagnostics must be rapid, precise, connectable, available at the point-of-care and effective in detecting both active disease and latent infection [6]. Molecular diagnostics and sequencing technology available today are powerful tools, but still need relatively sophisticated laboratory capacity, and are not offering a point of care solution thus limiting their efficacy in the field. Second, we need better, safer, shorter and more efficacious treatment for all forms of TB. The current research and development pipeline--although the most populated seen in the past few decades--still shows only less than 10 new agents in phase 1 trials, a handful of new drugs in phase 2 or 3 trials, and a few combination regimens being tested mainly for drug-resistant TB [7]. Completely new classes of anti-TB compounds are scarce, and potential synergistic combinations still unknown. Furthermore, targeting better treatment of active TB towards elimination goals is clearly not enough, as the reservoir of latent TB infection needs to be tackled as well. Mathematical models show that elimination may not be possible without targeting simultaneously latent infection and active disease [8]. Thus, addressing the vast pool of at-risk individuals among the estimated 1.7 billion people who may be latently infected is paramount, and solutions must be found that are simple and can be implemented safely among those at the highest risk of disease. Currently, the pipeline for treatment of latent infection includes a few trials using essentially known drugs such as isoniazid, rifampicin and rifapentine in different combinations, dosage and duration. Lastly, a vaccine would be the ultimate solution if found to be highly effective, safe, able to prevent pre-exposure infection as well as reactivation. However, at the moment, the most advanced and promising vaccine candidate among the 14 in the current pipeline offers at best a 50% protection among those with latent infection, and this still needs confirmation [9]. A fully effective potent vaccine is not envisaged for several years, and will certainly not be available on time to allow reaching the 2030 targets. Notwithstanding the importance of new, rapid diagnostics and efficacious vaccines, efforts to populate the pipeline and accelerate anti-TB drug research are a top priority for investors and researchers alike. Lately, after several years of stagnation, financial investments have been growing slowly passing 800 million US$ in 2019 [10]. However, this is far from sufficient to truly accelerate research toward new agents and regimens. The modest target of 2 billion US$/year, promoted within an existing international plan [11], is not at reach at the moment. At the same time, efforts in drug research begun in the early 2000s resulted in some successes with the discovery and development of agents such as bedaquiline and delamamid that are recommended for the treatment of drug-resistant TB. Recently, the combination of two new drugs--pretomamid and bedaquiline--with a re-purposed agent, linezolid, has resulted in unprecedented high rates of cure among advanced forms of multidrug-resistant TB (MDR-TB) and of extensively drug-resistant TB (XDR-TB) (Nix-TB trial) [12]. The demonstrated 90% cure rates observed in a single-arm, open-label trial in South Africa has prompted approval by the US Food and Drug Administration (FDA), despite the high frequency of adverse events, including bone marrow suppression and peripheral neuropathy, due to linezolid.