Killing of non-replicating Mycobacterium tuberculosis by 8-hydroxyquinoline

Objectives: To determine the effect of 8-hydroxyquinoline (8HQ) on non-replicating Mycobacterium tuberculosis (Mtb) in comparison with its reported effect on replicating Mtb. Methods: The MIC of 8HQ for replicating H37Rv Mtb was determined by microdilution in 7H9 broth. Bactericidal activity was determined by exposing H37Rv Mtb to 8HQ for 4 days under conditions that otherwise allowed exponential replication (20% O-2, pH 6.6) and conditions under which replication was precluded: 1% O-2, pH 6.6; 20% O-2, pH 5.5; or 20% O-2, pH 5.5, 0.5 mM sodium nitrite. Serial dilutions were plated on 7H11 agar to quantify cfu. Frequency of resistance (FOR) was determined with >10(9) bacteria plated on 7H9 agar plates containing 2x MIC 8HQ. Results: 8HQ was active against replicating Mtb (MIC 2.5 mu M, 0.36 mg/L). Under both replicating and non-replicating conditions, cfu were reduced in 4 days by >= 5 log(10) at the highest concentration tested (10 mu M). Bactericidal activity was maximal at low pH, where 8HQ reduced cfu by 1-1.5 log(10) at 1 mu M. We were unable to recover any 8HQ-resistant colonies. Conclusions: This study demonstrates that 8HQ has bactericidal activity of comparable potency against non-replicating and replicating Mtb, a property not observed for anti-infective agents currently approved for treatment of tuberculosis, and a very low FOR. Drugs with these properties are urgently needed to shorten the course of treatment for both active and latent tuberculosis.\