Carbonyl Cyanide 3-Chlorophenylhydrazone (CCCP) Exhibits Direct Antibacterial Activity Against Mycobacterium abscessus

Antibacterial activity of high-dose nitric oxide against pulmonary Mycobacterium abscessus disease

Access Microbiology ◽

10.1099/acmi.0.000154 ◽

2020 ◽

Vol 2 (9) ◽

Cited By ~ 1

Author(s):

Kristijan Bogdanovski ◽

Trisha Chau ◽

Chevalia J. Robinson ◽

Sandra D. MacDonald ◽

Ann M. Peterson ◽

...

Keyword(s):

Nitric Oxide ◽

Antibacterial Activity ◽

Type Species ◽

Mycobacterium Abscessus ◽

Clinical Isolates ◽

Content Type ◽

Link Type ◽

Susceptibility Tests ◽

Inhaled No

Introduction. Mycobacterium abscessus is an emerging pulmonary pathogen with limited treatment options. Nitric oxide (NO) demonstrates antibacterial activity against various bacterial species, including mycobacteria. In this study, we evaluated the effect of adjunctive inhaled NO therapy, using a novel NO generator, in a CF patient with pulmonary M. abscessus disease, and examined heterogeneity of response to NO in vitro. Methods. In the compassionate-use treatment, a 24-year-old CF patient with pulmonary M. abscessus was treated with two courses of adjunctive intermittent NO, first at 160 p.p.m. for 21 days and subsequently by escalating the dose up to 240 p.p.m. for 8 days. Methemoglobin, pulmonary function, 6 min walk distance (6MWD), qualify of life and sputum microbiology were assessed. In vitro susceptibility tests were performed against patient’s isolate and comparison clinical isolates and quantified by Hill’s slopes calculated from time–kill curves. Results. M. abscessus lung infection eradication was not achieved, but improvements in selected qualify of life domains, lung function and 6MWD were observed during the study. Inhaled NO was well tolerated at 160 p.p.m. Dosing at 240 p.p.m. was stopped due to adverse symptoms, although methemoglobin levels remained within safety thresholds. In vitro susceptibility tests showed a dose-dependent NO effect on M. abscessus susceptibility and significant heterogeneity in response between M. abscessus clinical isolates. The patient’s isolate was found to be the least susceptible strain in vitro. Conclusion. These results demonstrate heterogeneity in M. abscessus susceptibility to NO and suggest that longer treatment regimens could be required to see the reduction or eradication of more resistant pulmonary strains.

Download Full-text

AR-12 Exhibits Direct and Host-Targeted Antibacterial Activity toward Mycobacterium abscessus

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00236-20 ◽

2020 ◽

Vol 64 (8) ◽

Author(s):

Shaoyan Zhang ◽

Yuzhen Zou ◽

Qi Guo ◽

Jianhui Chen ◽

Liyun Xu ◽

...

Keyword(s):

Antibacterial Activity ◽

Minimum Bactericidal Concentration ◽

Bacterial Load ◽

Mycobacterium Abscessus ◽

Potential Candidate ◽

Content Type ◽

Repurposed Drugs ◽

Time Kill

ABSTRACT Therapeutic options for Mycobacterium abscessus infections are extremely limited. New or repurposed drugs are needed. The anti-M. abscessus activity of AR-12 (OSU-03012), reported to express broad-spectrum antimicrobial effects, was investigated in vitro and in vivo. Antimicrobial susceptibility testing was performed on 194 clinical isolates. Minimum bactericidal concentration and time-kill kinetics assays were conducted to distinguish the bactericidal versus bacteriostatic activity of AR-12. Synergy between AR-12 and five clinically important antibiotics was determined using a checkerboard synergy assay. The activity of AR-12 against intracellular M. abscessus residing within macrophage was also evaluated. Finally, the potency of AR-12 in vivo was determined in a neutropenic mouse model that mimics pulmonary M. abscessus infection. AR-12 exhibited high anti-M. abscessus activity in vitro, with an MIC50 of 4 mg/liter (8.7 μM) and an MIC90 of 8 mg/liter (17.4 μM) for both subsp. abscessus and subsp. massiliense. AR-12 and amikacin exhibited comparable bactericidal activity against extracellular M. abscessus in culture. AR-12, however, exhibited significantly greater intracellular antibacterial activity than amikacin and caused a significant reduction in the bacterial load in the lungs of neutropenic mice infected with M. abscessus. No antagonism between AR-12 and clarithromycin, amikacin, imipenem, cefoxitin, or tigecycline was evident. In conclusion, AR-12 is active against M. abscessus in vitro and in vivo and does not antagonize the most frequently used anti-M. abscessus drugs. As such, AR-12 is a potential candidate to include in novel strategies to treat M. abscessus infections.

Download Full-text

Dissecting the antibacterial activity of oxadiazolone-core derivatives against Mycobacterium abscessus

PLoS ONE ◽

10.1371/journal.pone.0238178 ◽

2020 ◽

Vol 15 (9) ◽

pp. e0238178 ◽

Cited By ~ 1

Author(s):

Abdeldjalil Madani ◽

Ivy Mallick ◽

Alexandre Guy ◽

Céline Crauste ◽

Thierry Durand ◽

...

Keyword(s):

Antibacterial Activity ◽

Mycobacterium Abscessus

Download Full-text

Antibacterial Activity of Human Neutrophil Defensin HNP-1 Analogs without Cysteines

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.11.4561-4566.2005 ◽

2005 ◽

Vol 49 (11) ◽

pp. 4561-4566 ◽

Cited By ~ 66

Author(s):

Jobin Varkey ◽

Ramakrishnan Nagaraj

Keyword(s):

Pseudomonas Aeruginosa ◽

Antibacterial Activity ◽

Human Neutrophil ◽

Therapeutic Agents ◽

Proton Motive Force ◽

Motive Force ◽

Gram Positive ◽

Gram Negative ◽

Gram Positive Bacteria ◽

Carbonyl Cyanide

ABSTRACT The antibacterial activity of human neutrophil defensin HNP-1 analogs without cysteines has been investigated. A peptide corresponding to the HNP-1 sequence without the six cysteines (HNP-1ΔC) exhibited antibacterial activity toward gram-negative and gram-positive bacteria. Truncated analogs wherein the nine N-terminal residues of HNP-1 and the remaining three cysteines were deleted (HNP-1ΔC18) or the G was replaced with A (HNP-1ΔC18A) also exhibited antibacterial activity. Substantial activity was observed for HNP-1ΔC and HNP-1ΔC18 in the presence of 100 mM NaCl, except in the case of Pseudomonas aeruginosa. The linear peptides were active in the presence of carbonyl cyanide m-chlorophenylhydrazone (CCCP), indicating that proton motive force was not essential for killing of bacteria by the peptides. In fact, in the presence of CCCP, the peptides were active against P. aeruginosa even in the presence of 100 mM NaCl. The antibacterial activity of HNP-1ΔC, but not that of the shorter, 18-residue peptides, was attenuated in the presence of serum. The generation of defensins without cysteines would be easier than that of disulfide-linked defensins. Hence, linear defensins could have potential as therapeutic agents.

Download Full-text

Antimicrobial and Efflux Inhibitor Activity of Usnic Acid Against Mycobacterium abscessus

Planta Medica ◽

10.1055/a-0639-5412 ◽

2018 ◽

Vol 84 (17) ◽

pp. 1265-1270 ◽

Cited By ~ 3

Author(s):

Ivy Ramis ◽

Júlia Vianna ◽

Ana Reis ◽

Andrea von Groll ◽

Daniela Ramos ◽

...

Keyword(s):

Antimicrobial Activity ◽

Antimicrobial Agent ◽

Natural Compound ◽

Usnic Acid ◽

Inhibitory Effect ◽

Mycobacterium Abscessus ◽

New Drugs ◽

Inhibitor Activity ◽

Carbonyl Cyanide

AbstractNew drugs are needed to treat infections with antimicrobial-resistant Mycobacterium abscessus; therefore, we evaluated usnic acid as an antimicrobial agent and efflux inhibitor (EI) against M. abscessus. Usnic acid showed antimicrobial activity, and synergistically, the EI verapamil increased this activity. In addition, when we evaluated the interaction of antimicrobials with usnic acid, the increase of their activity was observed. Finally, usnic acid showed an efflux inhibitory effect between the classical EIs verapamil and carbonyl cyanide m-chlorophenylhydrazine. In conclusion, usnic acid showed both antimicrobial and EI activity, indicating that this natural compound may be a promising scaffold for new drugs against this difficult-to-treat microorganism.

Download Full-text