**Angelo Iacobino, Lanfranco Fattorini \* and Federico Giannoni**

Istituto Superiore di Sanità, Department of Infectious Diseases, Via Regina Elena 299, 00161 Rome, Italy; angelo.iacobino@iss.it (A.I.); federico.giannoni@iss.it (F.G.)

**\*** Correspondence: lanfranco.fattorini@iss.it

Received: 3 March 2020; Accepted: 15 March 2020; Published: 22 March 2020

**Featured Application: This comprehensive overview of drug-resistant tuberculosis will be useful for researchers to expand their knowledge beyond mechanisms other than chromosomal mutations, and for the development of novel drugs**/**drug combinations, hoping to shorten the therapy of the disease.**

**Abstract:** The control of tuberculosis (TB) is hampered by the emergence of multidrug-resistant (MDR) *Mycobacterium tuberculosis* (Mtb) strains, defined as resistant to at least isoniazid and rifampin, the two bactericidal drugs essential for the treatment of the disease. Due to the worldwide estimate of almost half a million incident cases of MDR/rifampin-resistant TB, it is important to continuously update the knowledge on the mechanisms involved in the development of this phenomenon. Clinical, biological and microbiological reasons account for the generation of resistance, including: (i) nonadherence of patients to their therapy, and/or errors of physicians in therapy management, (ii) complexity and poor vascularization of granulomatous lesions, which obstruct drug distribution to some sites, resulting in resistance development, (iii) intrinsic drug resistance of tubercle bacilli, (iv) formation of non-replicating, drug-tolerant bacilli inside the granulomas, (v) development of mutations in Mtb genes, which are the most important molecular mechanisms of resistance. This review provides a comprehensive overview of these issues, and releases up-dated information on the therapeutic strategies recently endorsed and recommended by the World Health Organization to facilitate the clinical and microbiological management of drug-resistant TB at the global level, with attention also to the most recent diagnostic methods.

**Keywords:** tuberculosis; *Mycobacterium tuberculosis*; rifampin; isoniazid; mechanisms of resistance; mutations; granulomas; caseum; cell envelope; dormancy
