4.3.3. Other Mechanisms

The most important mechanisms of the intrinsic drug resistance of Mtb are considered to be the lipid-rich cell wall and the EP, but other systems are known to neutralize toxic chemicals and antibiotics, including drug inactivation or modification, and target modification.

Among drug inactivating enzymes, Mtb β-lactamases are less effective than those of other bacteria to hydrolyse β-lactams, but their activity, together with slow penetration across the cell wall and low affinity for penicillin-binding proteins, is good enough to render Mtb intrinsically resistant to most β-lactams [18,20]. The most important Mtb β-lactamase (BlaC) is thought to localize in the PS, and shows broad substrate specificity, including carbapenems, which are usually resistant to the β-lactamases of other bacteria. BlaC is inhibited by CLV that, as mentioned above, must be added to IPM- or MPM-containing prescriptions, as salvage WHO regimens for treatment of MDR/XDR-TB [8].

As to aminoglycosides (KM, AK) and cyclic peptides (CP), Mtb is able to inactivate them by acetylation performed by the enhanced intracellular survival protein encoded by *eis*, whose expression is upregulated by the MDR transcription regulator WhiB7 [20]. Promoter mutations lead to an overexpression of *eis*, resulting in low-level resistance to KM, but not AK [68].

*M. tuberculosis* is naturally resistant to macrolides (e.g., clarithromycin and azithromycin) because of the inducible erm(37), a ribosomal RNA methyltransferase which alters ribosomes by methylating the 23S rRNA [69,70]. Other*erm* genes conferring inducible resistance to FQs were found in non-tuberculous mycobacteria [71]. Intrinsic resistance to FQ is also attributed to a pentapeptide repeat protein called MfpA, which mimic the size, shape and surface charge of duplex DNA by resembling the 3D structure of a DNA double helix [20,72].

As to resistance to the broad-spectrum agent fosfomycin, Mtb is intrinsically resistant to this agent, which inhibits the MurA enzyme, involved in the biosynthesis of PG, because a cysteine residue in the active site of Mtb MurA is changed into aspartic acid [73].
