Pyrazinamide susceptibility and amidase activity of tubercle bacilli.

Abstract

Pyrazinamide, an analogue of nicotinamide, has the unique property of sterilizing large populations of M. tuberculosis with regularity when they have undergone previous or concurrent exposure to isoniazid in vivo (1). In long-term studies of this sterilization phenomenon (2), the few failures appear to be chiefly or wholly attributable to the emergence of tubercle bacilli resistant to pyrazinamide. It seemed appropriate, therefore, to focus on the resistance or susceptibility of tubercle bacilli to pyrazinamide as one approach to the study of the sterilization phenomenon. Tubercle bacilli of human or bovine origin are not inhibited by pyrazinamide or nicotinamide when tested in vitro in a neutral environment (3). Bacilli of human origin, however, have the capacity to become susceptible to either drug in vitro, when growing in either an acidic environment (pH 5.6) (3) or within monocytes in culture (4). The human bacilli (M. tuberculosis) are likewise inhibited in vivo by either drug (5, 6). By contrast, tubercle bacilli of bovine origin (M. bovis) are not inhibited in vivo by either drug and they lack the capacity to become drugsusceptible in vitro in either the cell-free acidic medium (3) or the monocytes (4). The bovine bacilli also show only a very low level of the amidase activity that in human bacilli converts pyrazinamide to pyrazinoic acid and nicotinamide to nicotinic acid. Indeed, this difference in