Mycobacterial Biofilm: Mechanisms, Clinical Problems, and Treatments

Abstract

Tuberculosis (TB) remains a threat to human health worldwide. Mycobacterium tuberculosis (Mtb) and other nontuberculous mycobacteria (NTM) can form biofilms, and in vitro and animal experiments have shown that biofilms cause serious drug resistance and mycobacterial persistence. Deeper investigations into the mechanisms of mycobacterial biofilm formation and, consequently, the exploration of appropriate antibiofilm treatments to improve the efficiency of current anti-TB drugs will be useful for curing TB. In this review, the genes and molecules that have been recently reported to be involved in mycobacterial biofilm development, such as ABC transporter, Pks1, PpiB, GroEL1, MprB, (p)ppGpp, poly(P), and c-di-GMP, are summarized. Biofilm-induced clinical problems, including biofilm-related infections and enhanced virulence, as well as their possible mechanisms, are also discussed in detail. Moreover, we also illustrate newly synthesized anti-TB agents that target mycobacterial biofilm, as well as some assistant methods with high efficiency in reducing biofilms in hosts, such as the use of nanoparticles.

Keywords: Mycobacterium tuberculosis; antibiofilm; biofilm; drug resistance; mycobacterial biofilm.

Figure 1

The interplay between poly (P) and (p)ppGpp. PPK1 promotes poly(P) synthesis through its polyphosphate kinase activity, while PPX1 hydrolyzes poly(P) with its exopolyphosphatase activity. PPK1 also promotes the production of (p)ppGpp by enhancing the transcription of mprAB and subsequently upregulating the expression of sigE and rel. The interplay between poly(P) and (p)ppGpp is reflected in two points. Firstly, Poly(P) enhances mprAB-sigE-rel signaling by phosphorylating MprA, thus upregulating the (p)ppGpp level. Secondly, (p)ppGpp displays an inhibiting effect on PPX1 and, consequently, promotes poly(P) accumulation. This figure was created with BioRender.com (accessed on 19 June 2024).

Figure 2

Anti-TB treatments in mice based on antibiofilm agents. Three strategies have been reported in current years. (1) Some antibiofilm formation agents, such as DMNP, trehalose analogs, and IDR1018, inhibit Mtb biofilm formation, enhancing the bactericidal activity of traditional anti-TB drugs. (2) Nanoparticles carrying IDR-1018 and traditional anti-TB drugs were coated with the mucus-penetrating agent NAC. After inhalation, it can penetrate host mucus via NAC and reach the infection points, releasing IDR-1018 and anti-TB drugs to prevent biofilm formation and kill planktonic Mtb cells. (3) Nanoparticles carrying cellulase and traditional anti-TB drugs were injected into host blood, which released cellulase and anti-TB drugs with the assistance of ultrasound irradiation. The formed mycobacterial biofilms were destroyed by cellulase, which improved the efficiency of anti-TB drugs. This figure was created with BioRender.com (accessed on 19 June 2024).