Action of 1-isonicotinyl-2-palmitoyl hydrazine against the Mycobacterium avium complex and enhancement of its activity by m-fluorophenylalanine

Abstract

In the present work, we investigated whether resistance to isoniazid (INH) of organisms belonging to the Mycobacterium avium complex was caused by the bacterial cell envelope, with the cell wall and the outer layer acting as an exclusion barrier. We observed that this exclusion barrier was most efficient in excluding the hydrophilic drug INH, as this drug could not penetrate a wall matrix formed of various polymethylated lipidic or amphipathic substances. Two main strategies were proposed for circumventing this drug resistance: (i) synthesis of amphipathic derivatives of otherwise highly hydrophilic drugs and (ii) inhibition of synthesis of the bacterial outer layer. The purpose of this work was to demonstrate that attaching a palmitic acid side chain to INH rendered it growth inhibitory against M. avium complex bacteria and that the concomitant use of this amphipathic INH derivative with m-fluorophenylalanine (an inhibitor of mycoside C biosynthesis which causes the disruption of the bacterial outer layer) resulted in further enhancement of its activity, leading to a bactericidal effect.