At the end of October 2022, the World Health Organization (WHO) published its Global Tuberculosis Report, pointing out that worldwide, this disease represents the 13th leading cause of death and the major infectious killer after SARS-CoV-2/COVID-19 and above HIV/AIDS [1]. Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb), whose pathogenic role was demonstrated in 1882 by the research conducted by Koch. TB is transmitted from person to person through the respiratory route, commonly affecting the lungs, but other tissues can also be damaged [2]. Estimations indicate that about a quarter of the world population is infected with Mtb during their lifetimes; however, most people will not develop TB, and in some cases, the infection can even be cleared [1]. Active TB might be manifested with mild symptoms during the first months, developing into a cough with sputum and sometimes blood, chest pains, general fatigue, weight loss, fever, and nocturnal sweating [1]. According to work on TB by Guinn and Rubin [3], published in a “frequently asked questions” (FAQs) format, pneumonia caused by Mtb exhibits two distinctive features: (1) the impairment of the lung tissue rather than the airways and (2) granuloma. Nonetheless, a major challenge against this disease relies on the bacterial capacity to remain latent and surprisingly persist in most infected individuals for a long time.

One distinguishing and, at the same time, outstanding feature of mycobacteria relies on the chemical nature and architecture of their cell wall. Mycobacterial cell walls are mainly composed of a peptidoglycan layer, mycolic acids, and arabinogalactan [4], rendering, in turn, their acid-fastness capacity and the low permeability to antimicrobial drugs (broad-spectrum antibiotics except for rifampicin). The knowledge about the acid-fast reaction of mycobacteria has mostly been derived from the Ziehl-Neelsen stain [5]. This structure plays a critical role for this class of bacteria, as crucial processes such as protection against hostile elements, mechanical resistance of the cells, solute and protein transport, and cell adhesion via the recognition of receptors take place here [6]. In addition to its role in the viability of Mtb, the chemical structure of its cell wall, particularly the peptidoglycan, renders unique molecular features that are important during dormancy [7].

The difference between active and latent TB, better identified as TB disease and latent TB infection, respectively, resides in the symptoms exhibited by the patients and their capacity to infect other people. In a journey through time (over two centuries), Behr et al. [8] addressed the confusion generated by different concepts related to latent TB and highlighted the relevance of using consistent definitions for research, treatments, and public health affairs. In this sense, patients with TB disease require multiple antibiotics/drug treatments for many months, depending on the regimen. Drug susceptible TB is treated by a 6-month standard course of 4 antibiotics: isoniazid (H), rifampicin (R), ethambutol (E), and pyrazinamide (Z); all four drugs are used for the first 2 months, and the remaining 4 are followed by H and R [1]. According to CDC [9], in the United States, treatments for TB disease shift in time length as follows: (1) 4-month rifapentine-moxifloxacin and (2) 6 or 9-month RIPE (rifampicin, isoniazid, pyrazinamide, and ethambutol). Together with rifabutin (Rbt), these four antibiotics represent the first line of drugs against TB [10]. Even though TB is a treatable disease, several complications are associated with its treatment. Adverse reactions to the medications include nausea, vomiting, loss of appetite, skin rashes, liver toxicity, or peripheral neuropathy, side effects that can affect treatment adherence and may require modifications to the drug regimen [11].

2. Tuberculosis as a Public Health Problem: An Old Challenge Still Present Due to Drug Resistance

From historical records, i.e., Egyptian and Peruvian mummies, it has been postulated that Mtb has infected human beings since very ancient times [12]. TB has a significant economic impact at the individual and social levels: (1) affecting children, the elderly, migrants, prisoners, and people living in poverty and (2) exacerbating health disparities ^[13][14][15,16]. In high-burden countries, many individuals with TB are asymptomatic in a latent state for many years and can be reactivated to cause disease [2]. Another setback of this illness relies on the fact that it affects vulnerable populations such as immunocompromised patients, which include cases positive for HIV/AIDS, malnourished individuals, and/or people with underlying health problems such as diabetes and cancer. In 1995, “Directly Observed Treatment” (DOT) was launched by WHO to ensure proper medication intake as prescribed and to monitor responses to treatment. Van Deun et al. ^[15][17] reported on a standardized program known as “the Bangladesh Regimen” consisting of kanamycin, gatifloxacin, prothionamide, high-dose isoniazid, clofazimine, pyrazinamide, and ethambutol for 9 to 11 months and attaining an 88% of success. Nevertheless, combining several drugs over long periods continues to be a struggle in completing treatment and enhancing the generation of resistant strains. Finally, in 2014, a new action plan called “End TB Strategy” was implemented. However, inadequate health services interfere with the timely diagnosis, treatment of the disease, and follow-up of TB cases, often leading to scheme failure and illness relapse and hindering the success of WHO’s strategies [1]. Drug-resistant TB (DR-TB), which can be broadly divided into intrinsic and acquired, poses an escalating worldwide threat to health security. Intrinsic resistance comprises the innate capacity to render antibacterial compounds less effective; meanwhile, in the specific case of Mtb, the acquired resistance is a result of specific chromosomal mutations ^[16][18]. Key mechanisms of drug resistance include loss of enzymatic action in the activation of pro-drugs, drug targets, overexpression of the drug target, and overexpression of the efflux pump. At a molecular level, research focused on finding genes responsible for drug resistance to isoniazid (katG), rifampin (rpoB), pyrazinamide (pncA), and quinolone (gyrA) has been conducted ^[17][19]. The emergence of drug-resistant TB, such as multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), complicates treatment and control efforts even further. Medicines used to treat drug-resistant strains often exhibit more toxicity, need longer treatment, and are more likely to present adverse effects. To make things worse, drug-resistant strains increase costs; for example, in patients with DR-TB, hospitalization was longer for cases exhibiting this feature compared to susceptible TB: 202 +/− 130 vs. 123 +/− 81 days (mean +/− SD; p = 0.015), respectively ^[18][20]. MDR-TB is defined as resistance to the two main first-line anti-TB drugs (isoniazid and rifampicin), while XDR-TB includes resistance to many second-line drugs, such as bedaquiline, linezolid, moxifloxacin, levofloxacin, clofazimine, cycloserine, para-aminosalicylic, propylthiouracil, and amikacin ^[19][21]. In addition, XDR-TB encompasses strains resistant to any fluoroquinolones and at least one of three injectable second-line drugs (amikacin, kanamycin, and/or capreomycin) ^[20][21][22,23]. MDR-TB requires the use of specific alternative TB chemotherapy regimens. These regimens involve the combination of second-line anti-tuberculosis drugs, which are typically more expensive and toxic and require longer durations. Alternatively, fluoroquinolones, better tolerated by patients, are central to the treatment of MDR-TB ^[22][24]. Prevention of transmission of MDR-TB and XDR-TB- requires robust TB control actions, including early diagnosis, appropriate treatment regimens, infection control measures, and monitoring systems for detection of drug resistance. Fighting against these challenging forms of DR-TB requires (1) ensuring universal access to quality TB care, (2) improving diagnostics, and (3) developing new anti-TB drugs and/or treatment regimens ^[23][25]. Of special interest in the field of bacterial resistance are mycobacteria transmitted via close contact with infected animals or via the consumption of contaminated products ^[24][26]. The Mycobacterium tuberculosis complex (MtbC) includes some mycobacteria that can cause zoonosis in humans. Alarmingly, among different species of the MtbC, some exhibit resistance to antibiotics used in the treatment of TB. Current research suggests that the transmission of MtbC is not only transmitted via the interfaces between humans and animals but also by the environment, including soil, water, pasture, air, dust, etc. ^[25][27]. A recent study found the presence of extracellular DNA (eDNA) in slow-growing mycobacteria, related to the formation of biofilms and the generation of resistance to isoniazid and amikacin ^[26][28]. Mtb could survive for extended periods in nature, which would make it easier for other mycobacteria to take eDNA directly from the environment and thus favor the appearance of new resistant strains. Actual methods for the diagnosis of tuberculosis are inefficient in differentiating Mtb from other mycobacteria, and this misleading diagnosis makes proper treatment impossible. The complications for correct diagnosis, the permanence of wild reservoirs, and the persistent infections in cattle have underestimated the number of actual cases of zoonosis, which, in addition, can have a significant impact on the natural course of TB ^[27][29].