Objectives: New antituberculosis agents active against drug-resistant and non-replicating tubercle bacilli are required. We evaluated a previously identified hit, 2-(((2-hydroxyphenyl)amino)methylene)-5,5-dimethylcyclohexane-1,3-dione (PAMCHD), against several clinical Mycobacterium tuberculosis isolates, including multidrug-resistant (MDR) strains and non-replicating drug-tolerant persisters of M. tuberculosis H37Rv.
Methods: PAMCHD's potential against drug-resistant M. tuberculosis was investigated by broth microdilution. CFU enumeration was performed to determine PAMCHD's activity against five types of dormant bacilli.
Results: No significant differences in MICs of PAMCHD were observed against M. tuberculosis H37Rv (2.5-5 µg/mL) and eight drug-susceptible strains (1.25-5 µg/mL) as well as drug-resistant strains including six isoniazid (INH)-resistant (2.5-10 µg/mL), one INH + ethambutol (EMB)-resistant (5 µg/mL), one rifampicin (RIF) + EMB-resistant (5 µg/mL) and three MDR (2.5-10 µg/mL) strains. Thus, PAMCHD maintains activity against all kinds of clinical strains, especially MDR. Regarding drug-tolerant persisters, INH and RIF killed, respectively, 0.5 and 5.0 log10 CFU of non-replicating persisters developed by hypoxia and 1.5 and 2.5 log CFU developed by nutrient starvation at 64 × of their respective MIC against actively dividing cultures. In contrast, PAMCHD sterilised persister cultures developed by hypoxia (killed 6.5 log10 CFU) or starvation (killed 7.5 log10 CFU). PAMCHD sterilised RIF-tolerant (tolerance level up to 100 µg/mL of RIF) 100-day-old static persisters at 64 × MIC, while moxifloxacin killed only 1.0 log10 CFU of these persisters at 64 × MIC.
Conclusion: PAMCHD offers significant potential against MDR-TB and exhibits notable potency against non-replicating drug-tolerant M. tuberculosis persisters. These findings warrant further studies of PAMCHD for further anti-TB drug development.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.jgar.2021.03.015 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Durlobactam in combination with β-lactams to combat .
Antimicrob Agents Chemother
December 2024
Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, USA.
() presents significant clinical challenges. This study evaluated the synergistic effects of a β-lactam and β-lactamase inhibitor combination against and explored the underlying mechanisms. Synergy was assessed through MIC tests and time-kill studies, and binding affinities of nine β-lactams and BLIs to eight target receptors (L,D-transpeptidases [LDT] 1-5, D,D-carboxypeptidase, penicillin-binding protein [PBP] B, and PBP-lipo) were assessed using mass spectrometry and kinetic studies.
View Article and Find Full Text PDFImipenem pharmacokinetics/pharmacodynamics in preclinical hollow fiber model, dose-finding in virtual patients, and clinical evidence of efficacy for Mycobacterium abscessus lung disease.
J Infect Dis
December 2024
Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Texas at Tyler, Tyler, Texas, USA.
Background: Guideline-based therapy (GBT) for Mycobacterium abscessus (Mab) lung disease achieves sputum culture conversion rates (SCC) of 35%. This poor GBT efficacy is mirrored in the hollow fiber system model of Mab (HFS-Mab). While imipenem is part of GBT, biological effect with or without β-lactamase inhibitors, is unproven.
View Article and Find Full Text PDFEarly bactericidal activity of sitafloxacin against pulmonary tuberculosis.
Microbiol Spectr
December 2024
Department of Bacteriology and Immunology, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis & Thoracic Tumor Research Institute, Beijing, China.
Sitafloxacin is a quinolone broad-spectrum antimicrobial agent, and its pharmacologic properties and data demonstrate that sitafloxacin has a potent killing effect against , including drug-resistant strains, which is superior to that of other available quinolones. However, its efficacy in patients with primary-sensitive tuberculosis is unclear. This study aims to evaluate the early bactericidal activity (EBA) of sitafloxacin in patients with primary drug-susceptible tuberculosis.
View Article and Find Full Text PDFComparative bactericidal activity of four macrolides alone and combined with rifampicin or doxycycline against at concentrations achievable in foals.
Front Pharmacol
November 2024
INTHERES, INRAE, ENVT, University of Toulouse, Toulouse, France.
Introduction: causes life-threatening respiratory disease in foals. The standard treatment typically involves a combination of rifampicin and a macrolide antibiotic. Although previous studies have demonstrated the activity of these antibiotics against , the tested concentrations often do not reflect those achievable in foals.
View Article and Find Full Text PDFExamining effective monotherapy hypothesis for TB therapy failure and resistance emergence.
Int J Tuberc Lung Dis
December 2024
Mathematical Modeling and AI, Praedicare Inc, Dallas, TX, USA;, Hollow Fiber System & Experimental Therapeutics Laboratories, Praedicare Inc, Dallas, TX, USA.
Article Synopsis
- The study investigated whether different metabolic states of Mycobacterium tuberculosis (Mtb) in lesions cause drugs used in combination therapy to act like they are used alone, potentially leading to therapy failure and drug resistance.
- The team tested various drug combinations, including isoniazid, rifampin, and pyrazinamide, using a hollow fiber system to see their effects on Mtb over 28 days.
- Results showed isoniazid was the most effective at killing Mtb, and no increase in drug-resistant strains was observed, suggesting that the emergence of resistance may not solely be due to the effectiveness of single-drug therapies.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!