Enhanced Killing of Intracellular Pathogenic Bacteria by Phenothiazines and the Role of K+ Efflux Pumps of the Bacterium and the Killing Macrophage

Pulmonary tuberculosis is an intracellular infection caused by Mycobacterium tuberculosis. Because its intracellular site is commonly the macrophage of the pulmonary system, and that cell has little killing action of its own, an antibiotic that is to be effective against this organism must be able to penetrate the macrophage and exert its action at the intracellular site where the organism resides. The anti-tubercular drugs which are most effective against this intracellular infection and which constitute the “first line of defence” are isoniazid and rifampin, both of which have activity against phagocytosed M. tuberculosis. Unfortunately, resistance to both of these agents (multi-drug resistant tuberculosis) continues to increase in frequency, and regardless of therapy, mortality is very high, nearing 100% within one year if the patient is co-infected with HIV or presents with AIDS. There is an obvious urgent need for effective anti-tubercular drugs. This review discusses the in vitro and ex vivo (phagocytosed bacteria) activity of phenothiazines and their derivatives and the mechanism by which these agents manifest their antibacterial activity in vitro and ex vivo. Because these and other agents promote the killing of intracellular bacteria by inhibiting the loss of K+ from the phagolysosome, it may be wiser to design drugs that enhance intracellular killing as opposed to those that have activity against the bacterium itself, since the latter approach will eventually be limited due to ensued resistance.