Solithera (solithromycin) / Melinta Therap, Fujifilm Holdings - LARVOL DELTA

Structural studies on ribosomes of differentially macrolide-resistant Staphylococcus aureus strains. (PubMed, Life Sci Alliance) - "Using cryo-electron microscopy, we determined the high-resolution structures of solithromycin-bound ribosomes, including those with dimethylated A2058. Our structural analysis reveals the specific interactions that enable solithromycin binding despite double methylation and resistance, as corroborated by microbiological and biochemical data, suggesting that further optimization of ketolide-ribosome interactions could enhance macrolide efficacy against resistant S. aureus strains."

Journal

In-vitro Activities of Zoliflodacin and Solithromycin Against Neisseria gonorrhoeae Isolates from Korea. (PubMed, Ann Lab Med) - "Most isolates (94.8%, 237/250) demonstrated non-susceptibility to penicillin G, tetracycline, and ciprofloxacin, and susceptibility to ceftriaxone and spectinomycin was substantially high. Zoliflodacin and solithromycin demonstrated significant in-vitro activity against multidrug-resistant N. gonorrhoeae isolates, and zoliflodacin has shown non-inferiority to ceftriaxone/azithromycin dual therapy in a clinical phase 3 trial. Collectively, our findings highlight the potential of zoliflodacin as a novel therapeutic agent for gonococcal infections, particularly in the context of rising multidrug resistance, and highlight the need for continued surveillance and development of alternative antimicrobial strategies."

Journal • Preclinical • Infectious Disease

Antibacterial compounds against non-growing and intracellular bacteria. (PubMed, NPJ Antimicrob Resist) - "Ten compounds - solithromycin, rifabutin, mitomycin C, and seven fluoroquinolones-have strong bactericidal activity against non-growing P. aeruginosa, killing >4 log10 of bacteria at 2.5 µM. Solithromycin, valnemulin, evofosfamide, and satraplatin are unique in their ability to selectively target non-growing bacteria, exhibiting poor efficacy against growing bacteria. Finally, 31 hit compounds inhibit the growth of intracellular Shigella flexneri in a human enterocyte infection model, indicating their ability to permeate the cytoplasm of host cells. The identified compounds hold potential for treating persistent infections, warranting further comparative studies with current standard-of-care antibiotics."

Journal • Infectious Disease • Oncology

Exploring the repurposed role of solithromycin as an antivirulence agent against Staphylococcus aureus and its resistant variants. (PubMed, Front Microbiol) - "PCR showed no leukocidin gene in the treated strains. This study highlights the potential of SOL as an antivirulence agent, emphasizing the importance of targeting regulators, such as ΔagrA, in managing S. aureus infections."

Journal • Infectious Disease

The Non-Antibacterial Effects of Azithromycin and Other Macrolides on the Bronchial Epithelial Barrier and Cellular Differentiation. (PubMed, Int J Mol Sci) - "Erythromycin, clarithromycin, roxithromycin, AZM, solithromycin, and tobramycin (an aminoglycoside) were analyzed using RNA sequencing, barrier integrity assays, and immunostaining to evaluate effects on the epithelium. Treatment with AZM, clarithromycin, and erythromycin raised TEER and induced phospholipid retention. AZM treatment was distinct in terms of enhancement of the epithelial barrier, retention of phospholipids, vesicle build-up, and its effect on gene sets related to keratinocyte differentiation and establishment of skin barrier."

Journal • Chronic Obstructive Pulmonary Disease • Immunology • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases

Pipeline of New Drug Treatment for Non-alcoholic Fatty Liver Disease/Metabolic Dysfunction-associated Steatotic Liver Disease. (PubMed, J Clin Transl Hepatol) - "Agents in this group include peroxisome proliferator-activated receptor agonists (e.g., pioglitazone, elafibranor, saroglitazar), bile acid-farnesoid X receptor axis regulators (obeticholic acid), de novo lipogenesis inhibitors (aramchol, NDI-010976), and fibroblast growth factor 21/19 analogs...Agents in this group include antioxidants (vitamin E), tumor necrosis factor α pathway regulators (emricasan, pentoxifylline, ZSP1601), and immune modulators (cenicriviroc, belapectin). The final group targets the gut (IMM-124e, solithromycin). Combination therapies targeting different pathogenetic pathways may provide an alternative to MASLD treatment with higher efficacy and fewer side effects. This review aimed to provide an update on these medications."

Journal • Review • Diabetes • Fibrosis • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Oncology • Type 2 Diabetes Mellitus • FGF21 • TNFA

Molecular and phenotypic characterization of Streptococcus pneumoniae isolates in a Japanese tertiary care hospital. (PubMed, Front Cell Infect Microbiol) - "Our study revealed the bacterial characteristics of the pneumococcal isolates obtained from our hospital. In vitro activity of solithromycin and lascufloxacin against these isolates was confirmed."

Journal • Infectious Disease • Pneumococcal Infections • Pneumonia

Engineering of a Malonyl-CoA Ligase for Production of Fluorinated Polyketide Extender Units. (PubMed, Chembiochem) - "However, despite broad interest in the fluorination of polyketides and prior success with engineering MatB homologs, the suitability of MatB for accessing the tertiary substituted fluoromethylmalonyl-CoA needed to produce flurithromycin and solithromycin has not yet been reported...Additionally, the mutant demonstrated broad utility for various substituted malonyl-CoAs. The MatB mutant sets the stage to access fluorinated macrolides by coupling it with altered PKS machinery to install fluorinated malonyl-CoA into macrolide scaffolds."

Journal

Solithromycin in Combination with Other Antimicrobial Agents Against the Carbapenem Resistant Klebsiella pneumoniae (CRKP). (PubMed, Indian J Microbiol) - "The combination study of solithromycin with meropenem, colistin, cefotaxime, piperacillin and tazobactam, nitrofurantoin, tetracycline, levofloxacin, curcumin and nalidixic acid was performed by using checkerboard assay. We observed the high rate of resistance towards ampicillin, cefotaxime, ceftriaxone, cefuroxime and aztreonam. The colistin and tigecycline were the most sensitive drugs...The best synergistic effect of solithromycin was with meropenem and cefotaxime (100%), colistin and tetracycline (80%). So, these combinations can be a choice of treatment for the infections caused by MDR CRKP and other Gram-negative bacteria where the monotherapy could not work."

Combination therapy • Journal • Critical care • Infectious Disease • Pneumonia • Respiratory Diseases

Synthesis and structure-activity relationships of novel 14-membered 2-fluoro ketolides with structural modification at the C11 position. (PubMed, Eur J Med Chem) - "A series of novel C11 substituted 14-membered 2-fluoro ketolides were synthesized and evaluated for their antibacterial activity against erythromycin-resistant and erythromycin-susceptible clinical isolates and strains from ATCC...Molecular docking suggested compound 12d oriented the macrolide ring and side chain similarly to solithromycin (SOL)...Therefore this research would offer a new perspective for further structural optimization of the C11 side chain. Based on the results of antibacterial activity, cytotoxicity and structural diversity, 5 compounds (11a, 11b, 11h, 12d and 12i) were selected for the stability testing of human liver microsomes and compound 11a exhibited preferable metabolic stability."

Journal • Infectious Disease • Influenza • Pneumonia • Respiratory Diseases

Macrolide and Ketolide Antibiotics Inhibit the Cytotoxic Effect of Trastuzumab Emtansine in HER2-Positive Breast Cancer Cells: Implication of a Potential Drug-ADC Interaction in Cancer Chemotherapy. (PubMed, Mol Pharm) - "Macrolides used in the clinic, such as roxithromycin, azithromycin, and josamycin, as well as solithromycin, a ketolide under clinical development, significantly attenuated T-DM1 cytotoxicity in addition to erythromycin and clarithromycin. These results suggest that the attenuation of T-DM1 cytotoxicity by macrolide and ketolide antibiotics involves their lysosomal accumulation and results in their greater lysosomal concentrations to inhibit the SLC46A3 function and T-DM1 degradation. This suggests a potential drug-ADC interaction during cancer chemotherapy."

Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Infectious Disease • Oncology • Solid Tumor • HER-2

Efficacy, safety, and tissue penetration of solithromycin in Japanese patients with otorhinolaryngological infections. (PubMed, Auris Nasus Larynx) - "Based on the findings, it is suggested that solithromycin is useful for the treatment of otorhinolaryngological infections."

Journal • Infectious Disease • Otorhinolaryngology • Respiratory Diseases • Sinusitis

Comparative analysis of macrolide antibiotics effects on bronchial epithelial cell differentiation in vitro (ERS 2023) - "In this study the non-antimicrobial effects of the traditional 14-membered macrolide antibiotics; erythromycin (ERY), clarithromycin (CLARI) and roxithromycin (ROXI), the 15-membered nitrogen containing macrolide, azithromycin (AZM) and the ketolide solithromycin (SOLI) were analyzed in vitro. Collectively, we have shown that macrolides have profound effects on gene expression and phenotype in human bronchial cells. AZM has distinctly greater epithelial barrier-inductive properties, although all macrolides tested affect gene expression, particularly gene sets involving inflammation, lipid metabolism and oxidative stress.; Respiratory intensive care; Public health; Pulmonary function testing; Cell and molecular biology; Epidemiology"

Preclinical • Critical care • Dermatology • Infectious Disease • Inflammation • Metabolic Disorders

New Resistance Mutations Linked to Decreased Susceptibility to Solithromycin in Streptococcus pneumoniae Revealed by Chemogenomic Screens. (PubMed, Antimicrob Agents Chemother) - "These included novel phenotypic mutations in the intergenic regions of the macrolide resistance locus mef(E)/mel and in the vicinity of the ribosome binding site of erm(B). Our screens highlighted that macrolide-resistant S. pneumoniae can easily acquire resistance to solithromycin, and they revealed many new phenotypic mutations."

Journal • Infectious Disease • Pneumococcal Infections • Pneumonia

Solithromycin inhibits IL-13-induced goblet cell hyperplasia and MUC5AC, CLCA1, and ANO1 in human bronchial epithelial cells. (PubMed, PeerJ) - "Our results indicate that solithromycin could attenuate goblet cell hyperplasia and MUC5AC induced by IL-13 through inhibition of CLCA1 and ANO1 mRNA and protein expression. However, much more information is required to clarify the molecular mechanisms underlying the inhibition of CLCA1 and ANO1 by solithromycin."

Journal • ANO1 • IL13 • MUC5AC • SPDEF

Solithromycin in Children and Adolescents With Community-acquired Bacterial Pneumonia. (PubMed, Pediatr Infect Dis J) - "Intravenous and oral solithromycin were generally well-tolerated and associated with clinical improvement in the majority of participants treated for CABP."

Clinical • Journal • Infectious Disease • Pain • Pediatrics • Pneumonia • Respiratory Diseases

The efficacy of solithromycin in a severe pneumonia model by Klebsiella pneumoniae (ECCMID 2022) - No abstract available

Clinical • Infectious Disease • Pneumonia • Respiratory Diseases

Alternative approaches utilizing click chemistry to develop next-generation analogs of solithromycin. (PubMed, Eur J Med Chem) - "Minimal inhibitory concentration assays were determined to assess the in vitro potency of the various analogs in relation to solithromycin. Two analogs exhibited improved activity compared to solithromycin against resistant strains, which can be assessed in further pre-clinical studies."

Journal • Infectious Disease • Pneumonia • Respiratory Diseases

Biocatalytic Asymmetric Construction of Secondary and Tertiary Fluorides from β-Fluoro-α-ketoacids. (PubMed, Angew Chem Int Ed Engl) - "However, stereogenic tertiary fluorides pose a synthetic challenge and are thus present in only a few approved drugs (fluticasone, solithromycin, and sofosbuvir). The reactivity of HpcH towards these fluoro-donors grants access to enantiopure secondary or tertiary fluorides. In addition to representing the first synthesis of tertiary fluorides via biocatalytic carboligation, the afforded products could improve the diversity of fluorinated building blocks and enable the synthesis of fluorinated drug analogs."

Journal

Fatty acid synthases (FASs) enable access to new-to-nature compounds (ACS-Sp 2022) - "(ii) The mammalian FASs features high transacylation rates for a wide range of substrates. We inserted the mammalian FAS transferase domain (MAT) into modular PKSs to enable the in vitro semisynthesis of new polyketides, including fluorinated polyketides with a macrolide scaffold similar to the next-generation antibiotic solithromycin (2-Fluoro-YC-17, see Figure).Semisynthetic approach to first produce the fluoro-methyl disubstituted macrolactone, which is then biotransformed to the fluorinated derivative of the antibiotic YC-17 using strain DHS316."

FASN

Discovery and Development of Antibacterial Agents: Fortuitous and Designed. (PubMed, Mini Rev Med Chem) - "These include solithromycin, plazomicin, lefamulin, omadacycline, eravacycline, delafloxacin, zabofloxacin, finafloxacin, nemonoxacin, gepotidacin, zoliflodacin, cefiderocol, BAL30072, avycaz, zerbaxa, vabomere, relebactam, tedizolid, cadazolid, sutezolid, triclosan and afabiacin. This article aims to review the investigational and recently approved antibacterials with a focus on their structure, mechanisms of action/resistance, and spectrum of activity. Delving deep, their success or otherwise in various phases of clinical trials is also discussed while attributing the same to various causal factors."

Journal

Azaindole Based Potentiator of Antibiotics against Gram-Negative Bacteria. (PubMed, ACS Infect Dis) - "We discovered azaindole-based compounds with weak innate activity that exhibit substantial potentiation of antibacterial activities of different antibiotics, viz., rifampicin, erythromycin, solithromycin, and novobiocin in Gram-negative bacteria. Our studies indicate that this selective potentiation is probably through destabilization of the outer membrane's integrity, known to be regulated by the lipopolysaccharides (LPS). Thus, the azaindole based compounds described here open opportunities for those antibiotics that are otherwise ineffective due to LPS mediated entry barriers in Gram-negative bacteria."

Journal • Infectious Disease • Pneumonia

Nationwide surveillance of the antimicrobial susceptibility of Chlamydia trachomatis from male urethritis in Japan: Comparison with the first surveillance report. (PubMed, J Infect Chemother) - "Based on serial cultures, the minimum inhibitory concentration (MIC) could be determined for 41 isolates; the MICs (MIC) of ciprofloxacin, levofloxacin, tosufloxacin, sitafloxacin, doxycycline, minocycline, erythromycin, clarithromycin, azithromycin and solithromycin were 2 μg/ml (2 μg/ml), 1 μg/ml (0.5 μg/ml), 0.25 μg/ml (0.25 μg/ml), 0.125 μg/ml (0.063 μg/ml), 0.125 μg/ml (0.125 μg/ml), 0.25 μg/ml (0.25 μg/ml), 0.031 μg/ml (0.031 μg/ml), 0.25 μg/ml (0.125 μg/ml), and 0.016 μg/ml (0.008 μg/ml), respectively. In summary, this surveillance project did not identify any strains resistant to fluoroquinolone, tetracycline, or macrolide agents in Japan...However, the MIC of azithromycin had a slightly higher value than that reported in the first surveillance report, though this might be within the acceptable margin of error. Therefore, the susceptibility of azithromycin, especially,..."

Journal • Infectious Disease

Synthesis, biological evaluation, and computational analysis of biaryl side-chain analogs of solithromycin. (PubMed, ChemMedChem) - "The biological activity of each analog was evaluated in terms of ribosomal affinity ( K d determined by fluorescence polarization), as well as minimum inhibitory concentration assays (MICs). Density functional theory (DFT) studies of a simple binding site model identify key H-bonding interactions that modulate the potency of solithromycin analogs."

Journal

Leveraging Physiologically-Based Pharmacokinetic (PBPK) Modeling and Experimental Data to Guide Dosing Modification of CYP3A-Mediated Drug-Drug Interactions (DDIs) in the Pediatric Population. (PubMed, Drug Metab Dispos) - "The geometric mean ratios for the simulated area under the concentration versus time curve (AUC) extrapolated to infinity were within 0.75-1.25-fold of observed values in healthy adults receiving solithromycin with midazolam or ketoconazole. In this study, minor age-related differences in inhibitor concentration resulted in differences in the magnitude of the DDI. Therefore, age-related differences in DDI potential for substrates metabolized primarily by CYP3A4 can be minimized by closely matching adult and pediatric inhibitor concentrations."

Clinical • Journal • PK/PD data • Infectious Disease • Pediatrics • Pneumonia • Respiratory Diseases • CYP3A4 • CYP3A5