The first cases of totally drug‐resistant (TDR) tuberculosis (TB) were reported in Italy 10 years ago; more recently, cases have also been reported in Iran, India and South Africa. Although there is no consensus on terminology, it is most commonly described as ‘resistance to all first‐ and second‐line drugs used to treat TB’. Mycobacterium tuberculosis (M.tb) acquires drug resistance mutations in a sequential fashion under suboptimal drug pressure due to monotherapy, inadequate dosing, treatment interruptions and drug interactions. The treatment of TDR‐TB includes antibiotics with disputed or minimal effectiveness against M.tb, and the fatality rate is high. Comorbidities such as diabetes and infection with human immunodeficiency virus further impact on TB treatment options and survival rates. Several new drug candidates with novel modes of action are under late‐stage clinical evaluation (e.g. delamanid, bedaquiline, SQ109 and sutezolid). ‘Repurposed’ antibiotics have also recently been included in the treatment of extensively drug resistant TB. However, because of mutations in M.tb, drugs will not provide a cure for TB in the long term. Adjunct TB therapies, including therapeutic vaccines, vitamin supplementation and/or repurposing of drugs targeting biologically and clinically relevant molecular pathways, may achieve better clinical outcomes in combination with standard chemotherapy. Here, we review broader perspectives of drug resistance in TB and potential adjunct treatment options.

Significance: Tuberculosis (TB) granulomas represent sites of both bacterial containment and tissue pathology. Macrophage killing of Mycobacterium tuberculosis ( Mtb ) in granulomas to contain infection must be regulated to prevent collateral tissue damage. Nitric oxide synthase-2 (NOS2) and arginase-1 (Arg1), macrophage enzymes metabolizing l -arginine, play key roles in this process. NOS2 produces reactive nitrogen intermediates to kill Mtb , whereas Arg1 regulates NOS2 activity via substrate competition. Arg1 activity could predominate in hypoxic regions of granulomas where NOS2 activity likely is suboptimal. Here we show that Arg1 plays a central role in restricting bacterial growth and restraining tissue damage within granulomas in TB and other chronic inflammatory diseases. These findings point to the modulation of Arg1 activity as a potential host-directed therapy for TB.

Summary: Mycobacterium tuberculosis (Mtb) is an aerobic bacterium that persists intracellularly in host macrophages and has evolved diverse mechanisms to combat and survive oxidative stress. Here we show a novel F₄₂₀‐dependent anti‐oxidant mechanism that protects Mtb against oxidative stress. Inactivation of the fbiC gene in Mtb results in a cofactor F₄₂₀‐deficient mutant that is hypersensitive to oxidative stress and exhibits a reduction in NADH/NAD⁺ ratios upon treatment with menadione. In agreement with the recent hypothesis on oxidative stress being an important component of the pathway resulting in cell death by bactericidal agents, F₄₂₀⁻ mutants are hypersensitive to mycobactericidal agents such as isoniazid, moxifloxacin and clofazimine that elevate oxidative stress. The Mtb deazaflavin‐dependent nitroreductase (Ddn) and its two homologues Rv1261c and Rv1558 encode for an F₄₂₀H₂‐dependent quinone reductase (Fqr) function leading to dihydroquinones. We hypothesize that Fqr proteins catalyse an F₄₂₀H₂‐specific obligate two‐electron reduction of endogenous quinones, thereby competing with the one‐electron reduction pathway and preventing the formation of harmful cytotoxic semiquinones, thus protecting mycobacteria against oxidative stress and bactericidal agents. These findings open up an avenue for the inhibition of the F₄₂₀ biosynthesis pathway or Fqr‐class proteins as a mechanism to potentiate the action of bactericidal agents.

Tuberculosis (TB) is an airborne infectious disease that kills almost two million individuals every year. Multidrug‐resistant (MDR) TB is caused by strains of Mycobacterium tuberculosis (M. tb) resistant to isoniazid and rifampin, the backbone of first‐line antitubercular treatment. MDR TB affects an estimated 500 000 new patients annually. Genetic analysis of drug‐resistant MDR‐TB showed that airborne transmission of undetected and untreated strains played a major role in disease outbreaks. The need for new TB vaccines and faster diagnostics, as well as the development of new drugs, has recently been highlighted. The major problem in terms of current TB research and clinical demands is the increasing number of cases of extensively drug‐resistant and ‘treatment‐refractory’ TB. An emerging scenario of adjunct host‐directed therapies is intended to target pulmonary TB where inflammatory processes can be deleterious and lead to immune exhaustion. ‘Target‐organ‐saving’ strategies may be warranted to prevent damage to infected tissues and achieve focused, clinically relevant and long‐lasting anti‐M. tb cellular immune responses. Candidates for such interventions may be biological agents or already approved drugs that can be ‘re‐purposed’ to interfere with biologically relevant cellular checkpoints. Here, we review current concepts of inflammation in TB disease and discuss candidate pathways for host‐directed therapies to achieve better clinical outcomes.