Thioridazine: A Non-Antibiotic Drug Highly Effective, in Combination with First Line Anti-Tuberculosis Drugs, against Any Form of Antibiotic Resistance of Mycobacterium tuberculosis Due to Its Multi-Mechanisms of Action

Abstract

This review presents the evidence that supports the use of thioridazine (TZ) for the therapy of a pulmonary tuberculosis infection regardless of its antibiotic resistance status. The evidence consists of in vitro and ex vivo assays that demonstrate the activity of TZ against all encountered Mycobacterium tuberculosis (Mtb) regardless of its antibiotic resistance phenotype, as well as in vivo as a therapy for mice infected with multi-drug resistant strains of Mtb, or for human subjects infected with extensively drug resistant (XDR) Mtb. The mechanisms of action by which TZ brings about successful therapeutic outcomes are presented in detail.

A Protein Complex from Human Milk Enhances the Activity of Antibiotics and Drugs against Mycobacterium tuberculosis

“…In particular, thioridazine was shown to synergize with TB drugs by enhancing the efficacy of isoniazid and rifampin by 64-and 128-fold (78), has sterilizing activity in combination with a first-line regimen against acute murine tuberculosis (79), and cured 17 out of 18 XDR-TB patients in Argentina (80). However, thioridazine and other phenothiazines inhibit Ca 2ϩ ion channels and are used as antipsychotic drugs (24); hence, they have side effects and are cytotoxic at low concentrations. For example, the 50% inhibitory concentration (IC 50 ) of thioridazine for human macrophages is 5 to 8 g/ml (24,78,81).…”

“…However, thioridazine and other phenothiazines inhibit Ca 2ϩ ion channels and are used as antipsychotic drugs (24); hence, they have side effects and are cytotoxic at low concentrations. For example, the 50% inhibitory concentration (IC 50 ) of thioridazine for human macrophages is 5 to 8 g/ml (24,78,81). An additional cytotoxic mechanism of many drug efflux pump inhibitors is that they impair host transporter proteins (82).…”

Oxidative Phosphorylation—an Update on a New, Essential Target Space for Drug Discovery in Mycobacterium tuberculosis

“…However, their limited potency coupled with an unfavourable toxicological profile preclude clinical use for TB treatment [99]. However, phenothiazines accumulate in macrophages and are particularly potent against intracellular M. tb [100,101]. Current efforts aim at developing new phenothiazine derivatives with improved activity against M. tb and reduced toxicity [102][103][104][105].…”

Dibasic Derivatives of Phenylcarbamic Acid Against Mycobacterial Strains: Old Drugs and New Tricks?

“…The treatment of commonly encountered species of tuberculous and non-tuberculous mycobacteria responsible for a multiplicity of different types of infections, including pulmonary, respiratory, cutaneous, and systemic infections, by (i) brand new classes of promising compounds preferably acting on novel targets; or (ii) ‘non-typical’ antimycobacterial drug candidates is still in very dynamic and progressive debate [ 1 , 2 , 3 , 4 , 5 , 6 ]. The strategy was successfully used in a case of in vitro screening of some β-lactam antibiotics (ceftaroline or ceftazidime) in a combination with an β-lactamase inhibitor avibactam against Mycobacterium avium complex [ 3 , 4 ].…”

“…Another encouraged example was in vitro and ex vivo testing of tricyclic thioridazine ( Figure 1 a), an old neuroleptic phenothiazine. The molecule was used alone or in a combinatorial therapy with anti-tuberculosis drugs (isoniazid, rifampin, linezolid or moxifloxacin) against M. tuberculosis regardless of its antibiotic resistance phenotype and was highly active due to its multi mechanisms of action [ 5 , 6 ].…”