Antibiotic Resistance to Mycobacterium tuberculosis and Potential Use of Natural and Biological Products as Alternative Anti-Mycobacterial Agents

Abstract

Tuberculosis (TB) is an infectious disease caused by the bacillus Mycobacterium tuberculosis (Mtb). TB treatment is based on the administration of three major antibiotics: isoniazid, rifampicin, and pyrazinamide. However, multi-drug resistant (MDR) Mtb strains are increasing around the world, thus, allowing TB to spread around the world. The stringent response is demonstrated by Mtb strains in order to survive under hostile circumstances, even including exposure to antibiotics. The stringent response is mediated by alarmones, which regulate bacterial replication, transcription and translation. Moreover, the Mtb cell wall contributes to the mechanism of antibiotic resistance along with efflux pump activation and biofilm formation. Immunity over the course of TB is managed by M1-macrophages and M2-macrophages, which regulate the immune response against Mtb infection, with the former exerting inflammatory reactions and the latter promoting an anti-inflammatory profile. T helper 1 cells via secretion of interferon (IFN)-gamma, play a protective role in the course of TB, while T regulatory cells secreting interleukin 10, are anti-inflammatory. Alternative therapeutic options against TB require further discussion. In view of the increasing number of MDR Mtb strains, attempts to replace antibiotics with natural and biological products have been object of intensive investigation. Therefore, in this review the anti-Mtb effects exerted by probiotics, polyphenols, antimicrobial peptides and IFN-gamma will be discussed. All the above cited compounds are endowed either with direct antibacterial activity or with anti-inflammatory and immunomodulating characteristics.

Keywords: antibiotic resistance; antibiotics; immunity; microbiota; multi-drug resistant Mycobacterium tuberculosis strains; stringent response.

Figure 1

Immune responsiveness during TB infection. Immunity to Mtb relies on a fine balance between inflammation (M1 macrophages) and anti-inflammation (M2 macrophages and TREG cells). Cytokines such as IL-12, IL-1-beta, TNF-alpha, and IL-10, according to their cellular source and disease stage, may play both beneficial and detrimental roles.

Figure 2

Mtb-induced mechanisms of antibiotic resistance. Stringent response elaborated by Mtb relies on Rel enzyme through the activity of alarmones. Synthesis of glycopeptidolipids contributes to the formation of biofilms, which increase resistance to antibiotics. Increased supply of amino acids allows Mtb to survive for years inside macrophages in the context of granuloma.

Figure 3

Potential use of natural products as anti-TB agents. Both probiotics and polyphenols have been experimented with as anti-TB pharmaceuticals. Probiotics can modulate the gut–lung axis that is compromised in the course of TB. Polyphenols exert anti-TB microbicidal activity in vitro and their application in human TB needs to be better explored.

Figure 4

Biotherapeutics for treatment of experimental and human TB. AMPs target Mtb in different ways, inhibiting intracellular mycobacterial growth and reducing pro-inflammatory cytokines and IL-12 release by Th1 cells. Nebulized, aerosol, subcutaneous, and intramuscular IFN-gamma administration leads to sputum conversion, reduction of fever, and improvement of life quality in severe human TB.