Crystal M Darby1, Carl F Nathan. 1. Department of Microbiology and Immunology, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
Abstract
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 microM, 0.36 mg/L). Under both replicating and non-replicating conditions, cfu were reduced in 4 days by > or = 5 log(10) at the highest concentration tested (10 microM). Bactericidal activity was maximal at low pH, where 8HQ reduced cfu by 1-1.5 log(10) at 1 microM. 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.
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 H37RvMtb was determined by microdilution in 7H9 broth. Bactericidal activity was determined by exposing H37RvMtb 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 microM, 0.36 mg/L). Under both replicating and non-replicating conditions, cfu were reduced in 4 days by > or = 5 log(10) at the highest concentration tested (10 microM). Bactericidal activity was maximal at low pH, where 8HQ reduced cfu by 1-1.5 log(10) at 1 microM. 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.
Authors: Santosh Shah; Alex G Dalecki; Aruni P Malalasekera; Cameron L Crawford; Suzanne M Michalek; Olaf Kutsch; Jim Sun; Stefan H Bossmann; Frank Wolschendorf Journal: Antimicrob Agents Chemother Date: 2016-09-23 Impact factor: 5.191
Authors: Ben Gold; Maneesh Pingle; Steven J Brickner; Nilesh Shah; Julia Roberts; Mark Rundell; W Clay Bracken; Thulasi Warrier; Selin Somersan; Aditya Venugopal; Crystal Darby; Xiuju Jiang; J David Warren; Joseph Fernandez; Ouathek Ouerfelli; Eric L Nuermberger; Amy Cunningham-Bussel; Poonam Rath; Tamutenda Chidawanyika; Haiteng Deng; Ronald Realubit; J Fraser Glickman; Carl F Nathan Journal: Proc Natl Acad Sci U S A Date: 2012-09-10 Impact factor: 11.205
Authors: Monika Krawczyk; Gabriela Pastuch-Gawołek; Aleksandra Pluta; Karol Erfurt; Adrian Domiński; Piotr Kurcok Journal: Molecules Date: 2019-11-18 Impact factor: 4.411
Authors: Francesco Russo; Johan Gising; Linda Åkerbladh; Annette K Roos; Agata Naworyta; Sherry L Mowbray; Anders Sokolowski; Ian Henderson; Torey Alling; Mai A Bailey; Megan Files; Tanya Parish; Anders Karlén; Mats Larhed Journal: ChemistryOpen Date: 2015-04-17 Impact factor: 2.911