Trifluoperazine inhibits the incorporation of labelled precursors into lipids, proteins and DNA of Mycobacterium tuberculosis H37Rv

Abstract

We have recently demonstrated that the calmodulin antagonist trifluoperazine has antitubercular activity in vitro against Mycobacterium tuberculosis H37Rv susceptible and resistant to isoniazid. It is now shown that trifluoperazine at a concentration of 50 micrograms ml-1 when added to the cells along with the labelled precursors inhibited the incorporation of [14C]acetate into lipids (63%) and uptake of [14C]glycine (74%) and [3H]thymidine (52%) by whole cells of M. tuberculosis H37Rv by 6 h of exposure. After 48 h, the inhibition was 87%, 97% and 74%, respectively. However, when the drug was added to cells taking up and metabolizing the labelled precursors at a later point (3 h for [14C]acetate and [3H]thymidine and 12 h for [14C]glycine) it inhibited completely the uptake of all the precursors, at least up to 24 h. The onset of inhibitory action was very rapid, i.e. 3 h. It is suggested that trifluoperazine has multiple sites of action and acts probably by affecting the synthesis of lipids, proteins and DNA.

Activity of Trifluoperazine against Replicating, Non-Replicating and Drug Resistant M. tuberculosis

“…Trifluoperazine (TFP) is a calmodulin antagonist in eukaryotes [3] and has been used as an antipsychotic drug in neuroleptic patients [4]. Though many reports have indicated antimycobacterial activity of TFP [5]–[7], its exact mechanism of action is not yet clearly understood. Phenothiazines have been reported to affect the calcium-dependent ATPases, thereby reducing the amount of cellular energy required to maintain the active transport processes [8]–[11].…”

Potential role of non-antibiotics (helper compounds) in the treatment of multidrug-resistant Gram-negative infections: mechanisms for their direct and indirect activities

“…Although the use of phenothiazines for therapy of Gramnegative infections is still very far from being seriously considered, phenothiazines appear to have great potential for the therapy of MDR tuberculosis (TB) [3,4,6,8,11]. As is the case for in vitro activity against Gram-negative bacteria, a large number of phenothiazines have been shown to have in vitro activity against Mycobacterium tuberculosis [14,[17][18][19][20]22,[80][81][82][83][84][85]. However, the concentrations of phenothiazines that inhibit in vitro growth cannot be achieved clinically [12].…”

“…Inhibition of intrinsic efflux of a noxious agent such as a phenothiazine is believed to result in greater permeability to other noxious agents, including the phenothiazine itself. Increased permeability ensures that phenothiazine molecules eventually reach the DNA, intercalate between the bases [103], inhibit all DNA-based processes [81] and hence inhibit replication. The in vitro concentrations of the phenothiazine that inhibit replication of the bacterium are generally many hundred-fold greater than that which can be achieved in the patient.…”

IMPLICATIONS OF ANTIBIOTIC RESISTANCES PRODUCED BY PHENOTHIAZINES IN Mycobacterium tuberculosis

“…Thus these observations on cross-resistance seem to be more easily explainable on the basis of a non-specific reduction in cell membrane permeability of the various Md and Pz mutants in varying degrees and selectivity with respects to different test drugs. A literature survey on the MICs of different antibiotics shows that there had been a significant rise in the highest values that characterize drug resistant strains as well as the lowest values of MICs of drugs/antibiotics (characterizing sensitive strains) with respect to almost all groups of pathogenic bacteria during the last five decades since the beginning of antibiotic era (Garrod and O' Grady, 1971;Ray et al, 1980). Development of such resistances has been ascribed to "intrinsic resistance" which is an evolutionary ancient phenotype and can be defined as resistance of any bacterial species to a particular drug/antibiotic that has not been acquired as a result of exposure to such agents (Fajardo et al, 2008).…”