The mechanisms and clinical potential of collateral sensitivity in Mycobacterium tuberculosis: A literature review

Tuberculosis (TB) is a global health issue, and the increasing resistance to anti-tuberculosis therapy (ATT) highlights the need for innovative treatment regimens. Among the different collateral effects of resistance development, collateral sensitivity (CS) is a phenomenon in which drug-resistant mutants display increased susceptibility to other drugs. The mechanisms of CS in Mycobacterium tuberculosis (MTB) include increased effective drug concentration due to altered transport proteins (MmpL3, MchK), disruption in pathways of cell wall synthesis (inhibited GlmR) and redox homeostasis (katG and mshA mutations), enhanced target affinity (EfpA), and downregulation of drug-deactivating enzymes (BlaC). Drugs that exploit CS include oxidative stress-inducing agents (isoniazid, ethionamide, bedaquiline, clofazimine, auranofin, thioacetazone, thiocarlide, etc.), efflux pump inhibitors (BRD 8000 and BRD 9327), rifampicin, beta-lactams, aminoglycosides (streptomycin, amikacin, and kanamycin), macrolides (erythromycin), and antimicrobial peptides. CS-based treatment strategies involve creating new drug combinations and drug cycling protocols to reduce the development of resistance, choosing drugs that exploit CS when resistance is present, and artificially emulating CS mechanisms by developing drugs that target novel molecular targets. Limitations of this concept include a lack of evolutionary conservation of CS, in vivo-exclusive pathogenic mutants, only slight reduction in minimum inhibitory concentrations, emergence of escape mutants, scarce data on horizontal resistance gene transfer in MTB, and a lack of clinical relevance of some tested compounds. However, the closed pan-genome and low intrinsic mutation rate of MTB could theoretically make CS-based regimens feasible. Still, the empirical evidence for such clinical use is lacking and future research could focus on it.