Rifalazil (benzoxazinorifamycin) / TrioBiotics Pharma - LARVOL DELTA

Adoption of an in-silico analysis approach to assess the functional and structural impacts of rpoB-encoded protein mutations on Chlamydia pneumoniae sensitivity to antibiotics. (PubMed, BMC Microbiol) - "The findings of this study indicate that mutations in the rpoB gene, which encodes the beta subunit of RNA polymerase, are pivotal in the resistance of C. pneumoniae to rifampin and rifalazil. Some of these mutations may result in reduced protein stability and changes in the structure, function, and antibiotic binding. As a consequence, the efficacy of these drugs in inhibiting RNA polymerase is compromised, allowing the bacteria to persist in transcription and replication even in the presence of antibiotics. Overall, these insights enhance our understanding of the resistance mechanisms in C. pneumoniae and could guide the development of strategies to address this challenge."

Journal • Infectious Disease • Pneumonia • Respiratory Diseases

Semi-synthesis and selective modification of natural product rifamycin S (ACS-Fall 2023) - "There are a number of commercially available rifamycin drugs including rifampicin, rifabutin, rifapentine, rifalazil and rifaximin, many of which are used as anti-tuberculosis (TB) drugs. All rifamycin S derived commercial antibiotics show substitution at the C3 position, and therefore this was the site of interest in our investigation.Through the successful formation of a C-I bond at the C3 position of rifamycin S, subsequent pd cross-couplings and SNAr have been undertaken, building a library of novel RIF derivatives. Further investigation into their activity towards RIF resistant TB strains showed promising results, comparable to current commercially available drugs."

Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

CRISPR Interference-Based Inhibition of MAB_0055c Expression Alters Drug Sensitivity in Mycobacterium abscessus. (PubMed, Microbiol Spectr) - "Our results showed that silencing the MAB_0055c gene lead to increased rifamycin susceptibility depending on the hydroquinone moiety...The study found that silencing the gene lead to increased rifabutin and rifalazil susceptibility...These findings underscore the potential of using CRISPRi as a tool for elucidating resistance mechanisms, essential drug targets, and drug mechanisms of action, which could pave the way for more effective treatments for M. abscessus infections. The results of this study could have important implications for the development of new therapeutic options for this challenging-to-treat bacterial infection."

Journal • Infectious Disease

Therapeutic efficacy of rifalazil (KRM-1648) in a M. ulcerans-induced Buruli ulcer mouse model. (PubMed, PLoS One) - "At the final point of the experiment, all the treated mice (5mg/kg/day; n = 6, 10mg/kg/day; n = 7) survived and had no signs of M. ulcerans infection. These results indicate that the rifamycin analogue, RLZ, is efficacious in the treatment of an advanced M. ulcerans infection mouse model."

Journal • Preclinical • Dermatology • Infectious Disease

Optimization of Benzoxazinorifamycins to Improve Mycobacterium tuberculosis RNA Polymerase Inhibition and Treatment of Tuberculosis. (PubMed, ACS Infect Dis) - "Rifampin (RMP), a very potent inhibitor of the Mycobacterium tuberculosis (MTB) RNA polymerase (RNAP), remains a keystone in the treatment of tuberculosis since its introduction in 1965...We have utilized a structure-based drug design approach to synthesize and test novel benzoxazinorifamycins (bxRIF), congeners of the clinical candidate rifalazil...These results suggest that 27a may exhibit a faster kill rate than RMP, which could possibly reduce the clinical treatment time. Our synthetic protocol enabled the synthesis of ∼2 g of 27a at >95% purity in 3 months, demonstrating the feasibility of scale-up synthesis of bxRIFs for preclinical and clinical studies."

Journal • Human Immunodeficiency Virus • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Optimization of Benzoxazinorifamycins to Minimize hPXR Activation for the Treatment of Tuberculosis and HIV Coinfection. (PubMed, ACS Infect Dis) - "Although the rifamycins (RIFs), best exemplified by the drug rifampin (RMP), represent a well-studied and therapeutically effective chemotype that targets the bacterial RNA polymerase (RNAP), these agents still suffer from serious drawbacks including the following: 3-9 month treatment times; cytochrome P450 (Cyp450) induction [particularly problematic for human immunodeficiency virus-Mycobacterium tuberculosis (MTB) co-infection]; and the existence of RIF-resistant (RIF) MTB strains. We have utilized a structure-based drug design approach to synthesize and test 15 benzoxazinorifamycins (bxRIFs), congeners of the clinical candidate rifalazil, to minimize human pregnane X receptor (hPXR) activation while improving potency against MTB...Importantly, we have analogues that are essentially equipotent against replicating MTB and non-replicating persister MTB, a property that is correlated with faster kill rates and may lead to shorter treatment durations. This work provides a..."

Journal • Human Immunodeficiency Virus • Immunology • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • CYP3A4

A Comparative Insight on the Newly Emerging Rifamycins: Rifametane, Rifalazil, TNP-2092 and TNP-2198. (PubMed, Curr Med Chem) - "Moreover, issues associated with rifamycins are discussed as well. We expect that newly emerging rifamycins shall appear as potential tools for TB treatment in the near future."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Non-standard treatment for uncomplicated Chlamydia trachomatis urogenital infections: a systematic review. (PubMed, BMJ Open) - "The paucity of existing data highlights the need for further adequately powered studies to evaluate rifalazil, delayed release doxycycline, levofloxacin and other agents for the treatment of uncomplicated CT infections."

Journal • Retrospective data • Review