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Development of a penem antibiotic against Mycobacteroides abscessus.

ABSTRACT: ?-lactams are the most widely used antibiotic class to treat bacterial infections in humans. Mycobacteroides abscessus is an emerging pulmonary pathogen resistant to most antibiotics, including penicillins and cephalosporins. With no current FDA-approved treatment and cure rates <50%, there is a pressing need for effective therapies. Here we report T405, a new ?-lactam of the penem subclass that exhibits potent activity against M. abscessus and a panel of drug-resistant strains isolated from cystic fibrosis patients. Additionally, in combination with the ?-lactamase inhibitor avibactam, the rate of spontaneous resistance of M. abscessus to T405 approached the limit of detection. Lastly, we show the favorable pharmacokinetic profile of T405 in mice and the absence of toxicity at elevated dosage, which support the clinical potential of this compound.

SUBMITTER: Batchelder HR

PROVIDER: S-EPMC7721803 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Development of a penem antibiotic against Mycobacteroides abscessus.

Batchelder Hunter R HR Story-Roller Elizabeth E Lloyd Evan P EP Kaushik Amit A Bigelow Kristina M KM Maggioncalda Emily C EC Nuermberger Eric L EL Lamichhane Gyanu G Townsend Craig A CA

Communications biology 20201207 1

β-lactams are the most widely used antibiotic class to treat bacterial infections in humans. Mycobacteroides abscessus is an emerging pulmonary pathogen resistant to most antibiotics, including penicillins and cephalosporins. With no current FDA-approved treatment and cure rates <50%, there is a pressing need for effective therapies. Here we report T405, a new β-lactam of the penem subclass that exhibits potent activity against M. abscessus and a panel of drug-resistant strains isolated from cys ...[more]

PMID: 33288821

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β-Lactam Combinations That Exhibit Synergy against Mycobacteroides abscessus Clinical Isolates.

Project description:Mycobacteroides abscessus (Mab) is an opportunistic environmental pathogen that can cause chronic pulmonary disease in the setting of structural lung conditions such as bronchiectasis, chronic obstructive pulmonary disease, and cystic fibrosis. These infections are often incurable and associated with rapid lung function decline. Mab is naturally resistant to most of the antibiotics available today, and current treatment guidelines require at least 1 year of daily multidrug therapy, which is often ineffective and is associated with significant toxicities. β-Lactams are the most widely used class of antibiotics and have a demonstrated record of safety and tolerability. Here, using a panel of recent clinical isolates of Mab, we evaluated the in vitro activities of dual-β-lactam combinations to identify new treatments with the potential to treat infections arising from a wide range of Mab strains. The Mab clinical isolates were heterogeneous, as reflected by the diversity of their genomes and differences in their susceptibilities to various drugs. Cefoxitin and imipenem are currently the only two β-lactams included in the guidelines for treating Mab disease, yet they are not used concurrently in clinical practice. However, this dual-β-lactam combination exhibited synergy against 100% of the isolates examined (n = 21). Equally surprising is the finding that the combination of two carbapenems, doripenem and imipenem, exhibited synergy against the majority of Mab isolates. In the setting of multidrug-resistant Mab disease with few therapeutic options, these combinations may offer viable immediate treatment options with efficacy against the broad spectrum of Mab strains infecting patients today.

| S-EPMC8097488 | biostudies-literature

Repurposing Avermectins and Milbemycins against Mycobacteroides abscessus and Other Nontuberculous Mycobacteria.

Project description:Infections caused by nontuberculous mycobacteria (NTM) are increasing worldwide, resulting in a new global health concern. NTM treatment is complex and requires combinations of several drugs for lengthy periods. In spite of this, NTM disease is often associated with poor treatment outcomes. The anti-parasitic family of macrocyclic lactones (ML) (divided in two subfamilies: avermectins and milbemycins) was previously described as having activity against mycobacteria, including Mycobacterium tuberculosis, Mycobacterium ulcerans, and Mycobacterium marinum, among others. Here, we aimed to characterize the in vitro anti-mycobacterial activity of ML against a wide range of NTM species, including Mycobacteroides abscessus. For this, Minimum Inhibitory Concentration (MIC) values of eight ML were determined against 80 strains belonging to nine different NTM species. Macrocyclic lactones showed variable ranges of anti-mycobacterial activity that were compound and species-dependent. Milbemycin oxime was the most active compound, displaying broad-spectrum activity with MIC lower than 8 mg/L. Time kill assays confirmed MIC data and showed bactericidal and sterilizing activity of some compounds. Macrocyclic lactones are available in many formulations and have been extensively used in veterinary and human medicine with suitable pharmacokinetics and safety properties. This information could be exploited to explore repurposing of anti-helminthics for NTM therapy.

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Designing a multi-epitope vaccine against Mycobacteroides abscessus by pangenome-reverse vaccinology.

Project description:Mycobacteroides abscessus (Previously Mycobacterium abscessus) is an emerging microorganism of the newly defined genera Mycobacteroides that causes mainly skin and tissue diseases in humans. The recent availability of total 34 fully sequenced genomes of different strains belonging to this species has provided an opportunity to utilize this genomics data to gain novel insights and guide the development of specific antimicrobial therapies. In the present study, we collected collectively 34 complete genome sequences of M. abscessus from the NCBI GenBank database. Pangenome analysis was conducted on these genomes to understand the genetic diversity and to obtain proteins associated with its core genome. These core proteins were then subjected to various subtractive filters to identify potential antigenic targets that were subjected to multi-epitope vaccine design. Our analysis projected the open pangenome of M. abscessus containing 3443 core genes. After applying various stepwise filtration steps on the core proteins, a total of four potential antigenic targets were identified. Utilizing their constituent CD4 and CD8 T-cell epitopes, a multi-epitope based subunit vaccine was computationally designed. Sequence-based analysis as well as structural characterization revealed the immunological effectiveness of this designed vaccine. Further molecular docking, molecular dynamics simulation and binding free energy estimation with Toll-like receptor 2 indicated strong structural associations of the vaccine with the immune receptor. The promising results are encouraging and need to be validated by additional wet laboratory studies for confirmation.

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New Mycobacteroides abscessus subsp. massiliense strains with recombinant hsp65 gene laterally transferred from Mycobacteroides abscessus subsp. abscessus: Potential for misidentification of M. abscessus strains with the hsp65-based method.

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| S-EPMC6743754 | biostudies-literature

A mouse model of pulmonary Mycobacteroides abscessus infection.

Project description:There is no preclinical mouse model to investigate pulmonary Mycobacteroides abscessus (formerly Mycobacterium abscessus) infection in an immunocompetent mouse strain, especially in the context of antibiotic testing and regimen development. We developed a mouse model of pulmonary M. abscessus infection using the aerosolized route of infection that leads to an increase in bacterial burden post- implantation and develops pathology as a result. In this mouse model, treatment with corticosteroid allows for initial proliferation and sustained M. abscessus pulmonary infection and permits evaluation of efficacies of antibiotics. Administration of corticosteroids that permitted higher levels of bacterial burden in the lungs were more likely to have pathology. Treatment of mice with antibiotics administered intranasally or subcutaneously significantly reduced lung M. abscessus burden. In addition to the reference strain, independent clinical isolates of M. abscessus also readily establish infection and proliferate in the lungs of mice in this model.

| S-EPMC7048719 | biostudies-literature

Genetic Determinants of Tigecycline Resistance in Mycobacteroides abscessus

Project description:Mycobacteroides abscessus (formerly Mycobacterium abscessus) is a clinically important, rapid-growing non-tuberculous mycobacterium notoriously known for its multidrug-resistance phenotype. The intrinsic resistance of M. abscessus towards first- and second-generation tetracyclines is mainly due to the over-expression of a tetracycline-degrading enzyme known as MabTetX (MAB_1496c). Tigecycline, a third-generation tetracycline, is a poor substrate for the MabTetX and does not induce the expression of this enzyme. Although tigecycline-resistant strains of M. abscessus have been documented in different parts of the world, their resistance determinants remain largely elusive. Recent work on tigecycline resistance or reduced susceptibility in M. abscessus revealed the involvement of the gene MAB_3508c which encodes the transcriptional activator WhiB7, as well as mutations in the sigH-rshA genes which control heat shock and oxidative-stress responses. The deletion of whiB7 has been observed to cause a 4-fold decrease in the minimum inhibitory concentration of tigecycline. In the absence of environmental stress, the SigH sigma factor (MAB_3543c) interacts with and is inhibited by the anti-sigma factor RshA (MAB_3542c). The disruption of the SigH-RshA interaction resulting from mutations and the subsequent up-regulation of SigH have been hypothesized to lead to tigecycline resistance in M. abscessus. In this review, the evidence for different genetic determinants reported to be linked to tigecycline resistance in M. abscessus was examined and discussed.

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Efficacy of epetraborole against <i>Mycobacteroides abscessus</i> in a mouse model of lung infection.

Project description:Mycobacteroides abscessus (Mab or Mycobacterium abscessus) is a fast-growing mycobacterium that is ubiquitous in the environment and can cause opportunistic disease in people with lung comorbidity and immunodeficiency. There are no Food and Drug Administration-approved drugs for this disease, and repurposed antibiotics have a poor microbiological response. To address the need for effective new antibiotics, we determined the efficacy of epetraborole (EBO) against three Mab clinical isolates in a mouse model of lung Mab infection. Reduction in lung Mab burden over 4 weeks of treatment was the study end point. EBO was administered orally once daily at doses of 25 and 50 mg/kg, which achieved exposures approximating the once-daily dosing of 250 mg and 500 mg, respectively, in humans. EBO administration led to a gradual reduction in the lung Mab burden. After 4 weeks of treatment, the efficacies of 25 and 50 mg/kg EBO against isolates ATCC 19977 and M9501 were comparable. However, against isolate M9530, 50 mg/kg EBO was more efficacious than 25 mg/kg and comparable with parenteral imipenem, one of the most efficacious antibiotics against Mab. We also undertook a dose-ranging study by evaluating the efficacies of once-daily oral administration of 0.5, 5, 10, 25, and 100 mg/kg EBO against M9501 over 4 weeks. Once-daily oral 100 mg/kg EBO was as effective as twice-daily 100 mg/kg imipenem injection. Our study suggests that EBO could address the unmet need for effective oral treatment options for Mab lung disease, given the high rates of Mab drug resistance and limited tolerable intravenous options.

| S-EPMC11323969 | biostudies-literature

Structure-Activity Relationship of Penem Antibiotic Side Chains Used against Mycobacteria Reveals Highly Active Compounds.

Project description:The rise of antibiotic-resistant Mycobacterium tuberculosis and non-tuberculous mycobacterial infections has placed ever-increasing importance on discovering new antibiotics to treat these diseases. Recently, a new penem, T405, was discovered to have strong antimicrobial activity against M. tuberculosis and Mycobacteroides abscessus. Here, a penem library of C2 side-chain variants was synthesized, and their antimicrobial activities were evaluated against M. tuberculosis H37Rv and M. abscessus ATCC 19977. Several new penems with antimicrobial activity stronger than the standard-of-care carbapenem antibiotics were identified with some candidates improving on the activity of the lead compound, T405. Moreover, many candidates showed little or no increase in the minimum inhibitory concentration in the presence of serum compared to the highly protein-bound T405. The penems with the strongest activity identified in this study were then biochemically characterized by reaction with the representative l,d-transpeptidase LdtMt2 and the representative penicillin-binding protein d,d-carboxypeptidase DacB2.

| S-EPMC10029149 | biostudies-literature

The synergetic effect of Imipenem-clarithromycin combination in the Mycobacteroides abscessus complex.

Project description:BACKGROUND:Nontuberculous mycobacteria (NTM) are ubiquitous organisms and the incidence of NTM infections has been increasing in recent years. Mycobacteroides abscessus (M. abscessus) is one of the most antimicrobial-resistant NTM; however, no reliable antibiotic regimen can be officially advocated. We evaluated the efficacy of clarithromycin in combination with various antimicrobial agents against the M. abscessus complex. RESULTS:Twenty-nine clinical strains of M. abscessus were isolated from various clinical samples. Of the isolates, 10 (34.5%) were of M. abscessus subsp. abscessus, 18 (62.1%) of M. abscessus subsp. massiliense, and 1 (3.4%) of M. abscessus subsp. bolletii. MICs of three antimicrobial agents (amikacin, imipenem, and moxifloxacin) were measured with or without clarithromycin. The imipenem-clarithromycin combination significantly reduced MICs compared to clarithromycin and imipenem monotherapies, including against resistant strains. The association between susceptibility of the M. abscessus complex and each combination of agents was significant (p?=?0.001). Adjusted residuals indicated that the imipenem-clarithromycin combination had the synergistic effect (adjusted residual?=?3.1) and suppressed the antagonistic effect (adjusted residual?=?-?3.1). In subspecies of M. abscessus complex, the association with susceptibility of M. abscessus subsp. massiliense was similarly statistically significant (p?=?0.036: adjusted residuals of synergistic and antagonistic effect respectively: 2.6 and?-?2.6). The association with susceptibility of M. abscessus subsp. abscessus also showed a similar trend but did not reach statistical significance. CONCLUSION:Our data suggest that the imipenem-clarithromycin combination could be the recommended therapeutic choice for the treatment of M. abscessus complex owing to its ability to restore antimicrobial susceptibility.

| S-EPMC7574464 | biostudies-literature

Potency of Omadacycline against Mycobacteroides abscessus Clinical Isolates <i>In Vitro</i> and in a Mouse Model of Pulmonary Infection.

Project description:The incidence of nontuberculous mycobacterial diseases in the United States is rising and has surpassed that of tuberculosis. Most notable among the nontuberculous mycobacteria is Mycobacteroides abscessus, an emerging environmental opportunistic pathogen capable of causing chronic infections. M. abscessus disease is difficult to treat, and the current treatment recommendations include repurposed antibiotics, several of which are associated with undesirable side effects. In this study, we have evaluated the activity of omadacycline, a new tetracycline derivative, against M. abscessus using in vitro and in vivo approaches. Omadacycline exhibited an MIC90 of 0.5 µg/mL against a panel of 32 contemporary M. abscessus clinical isolates, several of which were resistant to antibiotics that are commonly used for treatment of M. abscessus disease. Omadacycline combined with clarithromycin, azithromycin, cefdinir, rifabutin, or linezolid also exhibited synergism against several M. abscessus strains and did not exhibit antagonism when combined with an additional nine antibiotics also commonly considered to treat M. abscessus disease. Concentration-dependent activity of omadacycline was observed in time-kill assessments. Efficacy of omadacycline was evaluated in a mouse model of lung infection against four M. abscessus strains. A dose equivalent to the 300-mg standard oral human dose was used. Compared to the untreated control group, within 4 weeks of treatment, 1 to 3 log10 fewer M. abscessus CFU were observed in the lungs of mice treated with omadacycline. Treatment outcome was biphasic, with bactericidal activity observed after the first 2 weeks of treatment against all four M. abscessus strains.

| S-EPMC8765394 | biostudies-literature

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