scholarly journals Verapamil Improves the Activity of Bedaquiline against Mycobacterium abscessus In Vitro and in Macrophages

2019 ◽  
Vol 63 (9) ◽  
Author(s):  
Albertus Viljoen ◽  
Clément Raynaud ◽  
Matt D. Johansen ◽  
Françoise Roquet-Banères ◽  
Jean-Louis Herrmann ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Adjunctive Therapy ◽  
Mycobacterium Abscessus ◽  
Pulmonary Infections ◽  
Content Type ◽  
Resistant Strains ◽  
High Doses ◽  
Clinical Potential

ABSTRACT Due to intrinsic multidrug resistance, pulmonary infections with Mycobacterium abscessus are extremely difficult to treat. Previously, we demonstrated that bedaquiline is highly effective against Mycobacterium abscessus both in vitro and in vivo. Here, we report that verapamil improves the efficacy of bedaquiline activity against M. abscessus clinical isolates and low-level resistant strains, both in vitro and in macrophages. Verapamil may have clinical potential as adjunctive therapy provided that sufficiently high doses can be safely achieved.

scholarly journals Activity of LCB01-0371, a Novel Oxazolidinone, against Mycobacterium abscessus

2017 ◽  
Vol 61 (9) ◽  
Author(s):  
Tae Sung Kim ◽  
Jin Ho Choe ◽  
Young Jae Kim ◽  
Chul-Su Yang ◽  
Hyun-Jin Kwon ◽  
...  
Keyword(s):  
Similar Efficacy ◽  
Mycobacterium Abscessus ◽  
Sequencing Analysis ◽  
Highly Pathogenic ◽  
Content Type ◽  
New Class ◽  
Nucleotide Insertion ◽  
Resistant Strains

ABSTRACT Mycobacterium abscessus is a highly pathogenic drug-resistant rapidly growing mycobacterium. In this study, we evaluated the in vitro, intracellular, and in vivo activities of LCB01-0371, a novel and safe oxazolidinone derivative, for the treatment of M. abscessus infection and compared its resistance to that of other oxazolidinone drugs. LCB01-0371 was effective against several M. abscessus strains in vitro and in a macrophage model of infection. In the murine model, a similar efficacy to linezolid was achieved, especially in the lungs. We induced laboratory-generated resistance to LCB01-0371; sequencing analysis revealed mutations in rplC of T424C and G419A and a nucleotide insertion at the 503 position. Furthermore, LCB01-0371 inhibited the growth of amikacin-, cefoxitin-, and clarithromycin-resistant strains. Collectively, our data indicate that LCB01-0371 might represent a promising new class of oxazolidinones with improved safety, which may replace linezolid for the treatment of M. abscessus.

scholarly journals Bedaquiline Inhibits the ATP Synthase in Mycobacterium abscessus and Is Effective in Infected Zebrafish

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Christian Dupont ◽  
Albertus Viljoen ◽  
Sangeeta Thomas ◽  
Françoise Roquet-Banères ◽  
Jean-Louis Herrmann ◽  
...  
Keyword(s):  
Atp Synthase ◽  
Multidrug Resistant ◽  
Mycobacterium Abscessus ◽  
Nucleotide Polymorphisms ◽  
Pulmonary Infections ◽  
Zebrafish Model ◽  
Content Type ◽  
Short Period

ABSTRACT Pulmonary infections caused by Mycobacterium abscessus are emerging as a global threat, especially in cystic fibrosis patients. Further intensifying the concern of M. abscessus infection is the recent evidence of human-to-human transmission of the infection. M. abscessus is a naturally multidrug-resistant fast-growing pathogen for which pharmacological options are limited. Repurposing antitubercular drugs represents an attractive option for the development of chemotherapeutic alternatives against M. abscessus infections. Bedaquiline (BDQ), an ATP synthase inhibitor, has recently been approved for the treatment of multidrug-resistant tuberculosis. Herein, we show that BDQ has a very low MIC against a vast panel of clinical isolates. Despite being bacteriostatic in vitro, BDQ was highly efficacious in a zebrafish model of M. abscessus infection. Remarkably, a very short period of treatment was sufficient to protect the infected larvae from M. abscessus-induced killing. This was corroborated with reduced numbers of abscesses and cords, considered to be major pathophysiological signs in infected zebrafish. Mode-of-action studies revealed that BDQ triggered a rapid depletion of ATP in M. abscessus in vitro, consistent with the drug targeting the FoF1 ATP synthase. Importantly, despite a failure to select in vitro for spontaneous mutants that are highly resistant to BDQ, the transfer of single nucleotide polymorphisms leading to D29V or A64P substitutions in atpE conferred high resistance, thus resolving the target of BDQ in M. abscessus. Overall, this study indicates that BDQ is active against M. abscessus in vitro and in vivo and should be considered for clinical use against the difficult-to-manage M. abscessus pulmonary infections.

scholarly journals Effective Treatment of Mycobacterium avium subsp. hominissuis and Mycobacterium abscessus Species Infections in Macrophages, Biofilm, and Mice by Using Liposomal Ciprofloxacin

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
James D. Blanchard ◽  
Valerie Elias ◽  
David Cipolla ◽  
Igor Gonda ◽  
Luiz E. Bermudez
Keyword(s):  
Effective Treatment ◽  
Mouse Models ◽  
Mycobacterium Avium ◽  
Nontuberculous Mycobacteria ◽  
Mycobacterium Abscessus ◽  
Content Type ◽  
Number Of Individuals ◽  
Intranasal Instillation

ABSTRACT Nontuberculous mycobacteria (NTM) affect an increasing number of individuals worldwide. Infection with these organisms is more common in patients with chronic lung conditions, and treatment is challenging. Quinolones, such as ciprofloxacin, have been used to treat patients, but the results have not been encouraging. In this report, we evaluate novel formulations of liposome-encapsulated ciprofloxacin (liposomal ciprofloxacin) in vitro and in vivo. Its efficacy against Mycobacterium avium and Mycobacterium abscessus was examined in macrophages, in biofilms, and in vivo using intranasal instillation mouse models. Liposomal ciprofloxacin was significantly more active than free ciprofloxacin against both pathogens in macrophages and biofilms. When evaluated in vivo, treatment with the liposomal ciprofloxacin formulations was associated with significant decreases in the bacterial loads in the lungs of animals infected with M. avium and M. abscessus. In summary, topical delivery of liposomal ciprofloxacin in the lung at concentrations greater than those achieved in the serum can be effective in the treatment of NTM, and further evaluation is warranted.

scholarly journals Rifabutin Is Bactericidal against Intracellular and Extracellular Forms of Mycobacterium abscessus

2020 ◽  
Vol 64 (11) ◽  
Author(s):  
Matt D. Johansen ◽  
Wassim Daher ◽  
Françoise Roquet-Banères ◽  
Clément Raynaud ◽  
Matthéo Alcaraz ◽  
...  
Keyword(s):  
Opportunistic Pathogen ◽  
Mycobacterium Abscessus ◽  
Zebrafish Model ◽  
Content Type ◽  
Attractive Option ◽  
Conventional Antibiotics ◽  
Susceptibility Profiles ◽  
Combination Regimens

ABSTRACT Mycobacterium abscessus is increasingly recognized as an emerging opportunistic pathogen causing severe lung diseases. As it is intrinsically resistant to most conventional antibiotics, there is an unmet medical need for effective treatments. Repurposing of clinically validated pharmaceuticals represents an attractive option for the development of chemotherapeutic alternatives against M. abscessus infections. In this context, rifabutin (RFB) has been shown to be active against M. abscessus and has raised renewed interest in using rifamycins for the treatment of M. abscessus pulmonary diseases. Here, we compared the in vitro and in vivo activity of RFB against the smooth and rough variants of M. abscessus, differing in their susceptibility profiles to several drugs and physiopathologial characteristics. While the activity of RFB is greater against rough strains than in smooth strains in vitro, suggesting a role of the glycopeptidolipid layer in susceptibility to RFB, both variants were equally susceptible to RFB inside human macrophages. RFB treatment also led to a reduction in the number and size of intracellular and extracellular mycobacterial cords. Furthermore, RFB was highly effective in a zebrafish model of infection and protected the infected larvae from M. abscessus-induced killing. This was corroborated by a significant reduction in the overall bacterial burden, as well as decreased numbers of abscesses and cords, two major pathophysiological traits in infected zebrafish. This study indicates that RFB is active against M. abscessus both in vitro and in vivo, further supporting its potential usefulness as part of combination regimens targeting this difficult-to-treat mycobacterium.

scholarly journals Select β-Lactam Combinations Exhibit Synergy againstMycobacterium abscessus In Vitro

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Elizabeth Story-Roller ◽  
Emily C. Maggioncalda ◽  
Gyanu Lamichhane
Keyword(s):  
Treatment Options ◽  
Unmet Need ◽  
Mycobacterium Abscessus ◽  
Nontuberculous Mycobacterium ◽  
Pulmonary Infections ◽  
Content Type ◽  
Resistant Mutants ◽  
Lactamase Inhibitor ◽  
Selection Of

ABSTRACTMycobacterium abscessusis a nontuberculous mycobacterium that causes invasive pulmonary infections in patients with structural lung disease.M. abscessusis intrinsically resistant to several classes of antibiotics, and an increasing number of strains isolated from patients exhibit resistance to most antibiotics considered for treatment of infections by this mycobacterium. Therefore, there is an unmet need for new regimens with improved efficacy to treat this disease. Synthesis of the essential cell wall peptidoglycan inM. abscessusis achieved via two enzyme classes,l,d- andd,d-transpeptidases, with each class preferentially inhibited by different subclasses of β-lactam antibiotics. We hypothesized that a combination of two β-lactams that comprehensively inhibit the two enzyme classes will exhibit synergy in killingM. abscessus. Paired combinations of antibiotics tested forin vitrosynergy againstM. abscessusincluded dual β-lactams, a β-lactam and a β-lactamase inhibitor, and a β-lactam and a rifamycin. Of the initial 206 combinations screened, 24 pairs exhibited synergy. A total of 13/24 pairs were combinations of two β-lactams, and 12/24 pairs brought the MICs of both drugs to within the therapeutic range. Additionally, synergistic drug pairs significantly reduced the frequency of selection of spontaneous resistant mutants. These novel combinations of currently available antibiotics may offer viable immediate treatment options against highly-resistantM. abscessusinfections.

scholarly journals Sontochin as a Guide to the Development of Drugs against Chloroquine-Resistant Malaria

2012 ◽  
Vol 56 (7) ◽  
pp. 3475-3480 ◽  
Author(s):  
Sovitj Pou ◽  
Rolf W. Winter ◽  
Aaron Nilsen ◽  
Jane Xu Kelly ◽  
Yuexin Li ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Plasmodium Yoelii ◽  
Significant Activity ◽  
Drug Resistant ◽  
Content Type ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Derivatives Of

ABSTRACTSontochin was the original chloroquine replacement drug, arising from research by Hans Andersag 2 years after chloroquine (known as “resochin” at the time) had been shelved due to the mistaken perception that it was too toxic for human use. We were surprised to find that sontochin, i.e., 3-methyl-chloroquine, retains significant activity against chloroquine-resistant strains ofPlasmodium falciparum in vitro. We prepared derivatives of sontochin, “pharmachins,” with alkyl or aryl substituents at the 3 position and with alterations to the 4-position side chain to enhance activity against drug-resistant strains. Modified with an aryl substituent in the 3 position of the 7-chloro-quinoline ring, Pharmachin 203 (PH-203) exhibits low-nanomolar 50% inhibitory concentrations (IC50s) against drug-sensitive and multidrug-resistant strains andin vivoefficacy against patent infections ofPlasmodium yoeliiin mice that is superior to chloroquine. Our findings suggest that novel 3-position aryl pharmachin derivatives have the potential for use in treating drug resistant malaria.

scholarly journals Clomiphene Citrate Shows Effective and Sustained Antimicrobial Activity against Mycobacterium abscessus

2021 ◽  
Vol 22 (20) ◽  
pp. 11029
Author(s):  
Da-Gyum Lee ◽  
Yoo-Hyun Hwang ◽  
Eun-Jin Park ◽  
Jung-Hyun Kim ◽  
Sung-Weon Ryoo
Keyword(s):  
Clomiphene Citrate ◽  
Treatment Success ◽  
In Vitro Study ◽  
Drug Efficacy ◽  
Mycobacterium Abscessus ◽  
Pulmonary Infections ◽  
Wild Type ◽  
Antimicrobial Drugs ◽  
Resistant Strains

Mycobacterium abscessus (M. abscessus) causes chronic pulmonary infections and is the most difficult non-tuberculous mycobacteria (NTM) to treat due to its resistance to current antimicrobial drugs, with a treatment success rate of 45.6%. Thus, novel treatment drugs are needed, of which we identified the drug clomiphene citrate (CC), known to treat infertility in women, to exhibit inhibitory activity against M. abscessus. To assess the potential of CC as a treatment for M. abscessus pulmonary diseases, we measured its efficacy in vitro and established the intracellular activity of CC against M. abscessus in human macrophages. CC significantly inhibited the growth of not only wild-type M. abscessus strains but also clinical isolate strains and clarithromycin (CLR)-resistant strains of M. abscessus. CC’s drug efficacy did not have cytotoxicity in the infected macrophages. Furthermore, CC worked in anaerobic non-replicating conditions as well as in the presence of biofilm. The results of this in vitro study on M. abscessus activity suggest the possibility of using CC to develop new drug hypotheses for the treatment of M. abscessus infections.

scholarly journals Concurrent Local Delivery of Diflunisal Limits Bone Destruction but Fails To Improve Systemic Vancomycin Efficacy during Staphylococcus aureus Osteomyelitis

2020 ◽  
Vol 64 (7) ◽  
Author(s):  
Thomas J. Spoonmore ◽  
Caleb A. Ford ◽  
Jacob M. Curry ◽  
Scott A. Guelcher ◽  
James E. Cassat
Keyword(s):  
Staphylococcus Aureus ◽  
Adjunctive Therapy ◽  
Bone Destruction ◽  
Standard Of Care ◽  
Quorum Quenching ◽  
Toxin Production ◽  
Local Drug Delivery ◽  
Content Type

ABSTRACT Staphylococcus aureus osteomyelitis is a debilitating infection of bone. Treatment of osteomyelitis is impaired by the propensity of invading bacteria to induce pathological bone remodeling that may limit antibiotic penetration to the infectious focus. The nonsteroidal anti-inflammatory drug diflunisal was previously identified as an osteoprotective adjunctive therapy for osteomyelitis, based on the ability of this compound to inhibit S. aureus quorum sensing and subsequent quorum-dependent toxin production. When delivered locally during experimental osteomyelitis, diflunisal significantly limits bone destruction without affecting bacterial burdens. However, because diflunisal’s “quorum-quenching” activity could theoretically increase antibiotic recalcitrance, it is critically important to evaluate this adjunctive therapy in the context of standard-of-care antibiotics. The objective of this study is to evaluate the efficacy of vancomycin to treat osteomyelitis during local diflunisal treatment. We first determined that systemic vancomycin effectively reduces bacterial burdens in a murine model of osteomyelitis and identified a dosing regimen that decreases bacterial burdens without eradicating infection. Using this dosing scheme, we found that vancomycin activity is unaffected by the presence of diflunisal in vitro and in vivo. Similarly, locally delivered diflunisal still potently inhibits osteoblast cytotoxicity in vitro and bone destruction in vivo in the presence of subtherapeutic vancomycin. However, we also found that the resorbable polyester urethane (PUR) foams used to deliver diflunisal serve as a nidus for infection. Taken together, these data demonstrate that diflunisal does not significantly impact standard-of-care antibiotic therapy for S. aureus osteomyelitis, but they also highlight potential pitfalls encountered with local drug delivery.

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

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.

scholarly journals Synergistic Efficacy of β-Lactam Combinations againstMycobacterium abscessusPulmonary Infection in Mice

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Elizabeth Story-Roller ◽  
Emily C. Maggioncalda ◽  
Gyanu Lamichhane
Keyword(s):  
Acquired Resistance ◽  
Mycobacterium Abscessus ◽  
The Novel ◽  
Content Type ◽  
Treatment Regimens ◽  
Chronic Lung Diseases ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Inhibitor Combination

ABSTRACTMycobacterium abscessusis an emerging pathogen capable of causing invasive pulmonary infections in patients with chronic lung diseases. These infections are difficult to treat, necessitating prolonged multidrug therapy, which is further complicated by extensive intrinsic and acquired resistance exhibited by clinicalM. abscessusisolates. Therefore, development of novel treatment regimens effective against drug-resistant strains is crucial. Prior studies have demonstrated synergistic efficacy of several β-lactams againstM. abscessusin vitro; however, these combinations have never been tested in an animal model ofM. abscessuspulmonary disease. We utilized a recently developed murine system of sustainedM. abscessuslung infection delivered via an aerosol route to test the bactericidal efficacy of four novel dual β-lactam combinations and one β-lactam/β-lactamase inhibitor combination. All five of the novel combinations exhibited synergy and resulted in at least 6-log10reductions in bacterial burden in the lungs of mice at 4 weeks compared to untreated controls (P = 0.038).

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