iclaprim (MTF-100) / Motif Bio - LARVOL DELTA

High throughput screening identifies potential inhibitors targeting trimethoprim resistant DfrA1 protein in Klebsiella pneumoniae and Escherichia coli. (PubMed, Sci Rep) - "These interactions were comparable to those of Iclaprim, a well-known antibiotic effective against DfrA1...Overall, findings of this study suggest that DC4 and DC6 have the potential to act as inhibitors against the DfrA1, offering promising prospects for the treatment and management of infections caused by trimethoprim-resistant K. pneumoniae and E. coli in both humans and animals. However, further in vitro validations are necessary."

Journal • Infectious Disease • Pneumonia • DHFR

Anti-virulence potential of iclaprim, a novel folic acid synthesis inhibitor, against Staphylococcus aureus. (PubMed, Appl Microbiol Biotechnol) - "The findings suggest that iclaprim may have potential as an anti-virulence and antibiofilm agent, thus potentially mitigating the pathogenicity of S. aureus and improving clinical outcomes associated with infections caused by this pathogen. KEY POINTS: • Iclaprim effectively inhibits α-hemolysin production and biofilm formation in a strain-dependent manner and was an excellent depolymerizing agent of mature biofilm • Iclaprim affected the mRNA expression of virulence-encoding genes associated with exoproteins, adherence, and regulation • In vivo study in G. mellonella larvae challenged with S. aureus exhibited that iclaprim improves larvae survival."

Journal • Infectious Disease

Resistance to antibacterial antifolates in multidrug-resistant Staphylococcus aureus: prevalence estimates and genetic basis. (PubMed, J Antimicrob Chemother) - "This study provides a detailed picture of the genotypes underlying staphylococcal resistance to antifolate drugs in clinical use and in development. Prevalence estimates suggest that resistance to the diaminopyrimidines (trimethoprim/iclaprim) is not uncommon among MDR S. aureus, and considerably higher than observed for sulfamethoxazole or co-trimoxazole."

Journal • Infectious Disease • DHFR

Iclaprim mesylate displaying a hydrogen-bonded mol-ecular tape. (PubMed, Acta Crystallogr E Crystallogr Commun) - "Four distinct N-H⋯O inter-actions and an additional N-H⋯N hydrogen bond connect iclaprim and mesylate mol-ecules to one another, resulting in an infinite hydrogen-bonded mol-ecular tape structure. The central section of the tape is formed by a sequence of fused hydrogen-bonded rings involving four distinct ring types."

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Efficacy and Safety of Iclaprim for the Treatment of Skin Structures and Soft Tissue Infections: A Methodological Framework. (PubMed, Front Pharmacol) - "Ethics and Dissemination: This systematic review and meta-analysis will be based on published data, so ethical approval is not necessary. The results of this meta-analysis will be published in a peer-reviewed journal."

Journal • Dermatology • Infectious Disease

Hypoxic tubular epithelial cells regulate the angiogenesis of HMEC-1 cells via mediation of Rab7/MMP-2 axis. (PubMed, Aging (Albany NY)) - "Moreover, ARP100 (MMP-2 inhibitor) significantly reversed the effect of Rab7 shRNA on cell viability, migration and angiogenesis...Knockdown of Rab7 significantly alleviated the renal hypoxia in chronic kidney disease through regulation of MMP-2. Thus, our study might shed new light on exploring the new strategies against CKD."

Journal • Chronic Kidney Disease • Fibrosis • Immunology • Nephrology • Renal Disease • MMP2

Comparative efficacy of delafloxacin for complicated and acute bacterial skin and skin structure infections: results from a network meta-analysis. (PubMed, BMC Infect Dis) - "Delafloxacin is a promising new antibiotic for ABSSSI demonstrating greater improvement (composite clinical response) compared to ceftobiprole, fusidic acid, iclaprim, telavancin and vancomycin and comparable effectiveness versus standard of care for all outcomes considered in the study."

Clinical • Journal • Retrospective data • Dermatology • Infectious Disease • Obesity

SerpinA3N deficiency deteriorates impairments of learning and memory in mice following hippocampal stab injury. (PubMed, Cell Death Discov) - "We further show that MMP2 is a key substrate of SerpinA3N, and MMP2 specific inhibitor (ARP100) can protect against neuronal apoptosis and cognitive dysfunction in mice after HSI. These findings demonstrate a critical role for SerpinA3N in neuroprotection, suggesting that SerpinA3N and MMP2 inhibitors might be a novel therapeutic agents for neurotrauma."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Vascular Neurology • MMP2

Single-component and two-component para-nitrophenol monooxygenases: structural basis for their catalytic difference. (PubMed, Appl Environ Microbiol) - "Aerobic microbial degradation of PNP has been classically shown to proceed via 'Hydroquinone (HQ) pathway' in Gram-negative degraders, whereas via 'Benzenetriol (BT) pathway' in Gram-positive ones...The crystal structure and site-directed mutagenesis underlined the direct involvement of Arg100 and His293 in catalysis...Moreover, through comparing the two types of PNP monooxygenases, a hypothesis was proposed to account for their catalytic difference, which gives us a better understanding of these two similar reactions at molecular level. And these results will also be of further aid in enzyme rational design in bioremediation and biosynthesis."

Journal • Infectious Disease

Identification and characterization of inheritable structural variations induced by ion beam radiations in rice. (PubMed, Mutat Res) - "In the present study, we identified and validated SVs in six M plants (designated as Ar_50, Ar_100, C_150, C_200, Ne_50 and Ne_100 according to ion beam types and irradiation doses), two each induced by argon (Ar), carbon (C) and neon (Ne) ion beams and performed in depth analyses of their characteristics...Three mechanisms might be involved in the SV formation, i.e., the expansion of tandem repeats, transposable element insertion, and non-allelic homologous recombination. Put together, the present study provides a preliminary view of SVs induced by Ar, C and Ne ion beam radiations, and as a pilot study, it contributes to our understanding of how SVs might form after ion beam irradiation in rice."

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Minimum-inhibitory-concentration of iclaprim and lefamulin against Mycobacterium abscessus complex. (PubMed, Antimicrob Agents Chemother) - "Infections with rapid-growing-mycobacteria (RGM) are often difficult to treat.…."

Journal • Infectious Disease

[VIRTUAL] Antibiotic Combination Eradicates All Bacterial Pathogens Associated with Wound Infection (WMF 2021) - "We found that a combination of SPR206/iclaprim resulted in MICs ranging from 0.00325 - 0.25 µg/mL against the ESKAPEE pathogens. Specifically, E. coli and Enterobacter were the most susceptible; this broad-spectrum coverage is the true utility of the combination. Time-kills at the MIC show that drugs alone result in some bacterial growth, regrowth of persisters, but the combination is bactericidal."

Infectious Disease • Pneumonia • Septic Shock

Expression pattern and prognostic impact of glycoprotein non-metastatic B (GPNMB) in triple-negative breast cancer. (PubMed, Sci Rep) - "GPNMB-enhanced cell invasion was attenuated by broad spectrum MMP inhibitor (GM 6001) and the selective inhibitor of MMP-2 (ARP100). In summary, GPNMB expression is prevalent in TNBC and may be implicated as a prognostic biomarker in patients with TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • MMP2 • VIM

In vitro activity of Iclaprim and comparator agents against Listeria monocytogenes clinical isolates from 2012-2018. (PubMed, J Glob Antimicrob Resist) - "Iclaprim demonstrated lower MIC values than trimethoprim against a collection (2012-2018) of L. monocytogenes clinical isolates mostly from patients with blood stream infections from the United States, Australia/New Zealand, Latin America, and Europe."

Journal • DHFR

The activity of the diaminopyrimidine dihydrofolate reducatase inhibitor, iclaprim, against Toxoplasma gondii in an in vitro model: a pilot study. (PubMed, Diagn Microbiol Infect Dis) - "In addition, iclaprim exhibited synergy in vitro when tested in the presence of sulfamethoxazole. Iclaprim should be further investigated as an agent for the treatment or prophylaxis of toxoplasmosis."

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Worldwide surveillance of Iclaprim activity: In Vitro susceptibility of gram-positive pathogens collected from patients with skin and skin structure infections from 2013 to 2017. (PubMed, Diagn Microbiol Infect Dis) - "The MIC for iclaprim was 8 to 32-fold lower than trimethoprim, the only FDA approved dihydrofolate reductase inhibitor, against all Gram-positive isolates including resistant phenotypes. Iclaprim demonstrated lower MICs than trimethoprim against a collection (2013-2017) of Gram-positive clinical isolates from patients with SSSI from the United States, Asia Pacific, Latin America, and Europe."

Journal • Infectious Disease

SerpinA3N deficiency deteriorates impairments of learning and memory in mice following hippocampal stab injury. (PubMed, Cell Death Discov) - "We further show that MMP2 is a key substrate of SerpinA3N, and MMP2 specific inhibitor (ARP100) can protect against neuronal apoptosis and cognitive dysfunction in mice after HSI. These findings demonstrate a critical role for SerpinA3N in neuroprotection, suggesting that SerpinA3N and MMP2 inhibitors might be a novel therapeutic agents for neurotrauma."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Vascular Neurology • MMP2

Iclaprim reduces the incidence and severity of Staphylococcus aureus-induced septic arthritis in a murine model. (PubMed, Access Microbiol) - "The efficacy of iclaprim against S. aureus LS-1, a clinical strain identified from a patient with septic arthritis, was studied in MF1 mice to evaluate the activity of iclaprim, which is in clinical development, in preventing joint infections. Iclaprim (2.5-80 mg kg) administered as a single dose via the tail vein reduced the incidence of S. aureus septic arthritis and mortality in an experimental murine model of septic arthritis."

Journal • Preclinical • Immunology • Rheumatology

An efficacy analysis by lesion size of iclaprim versus vancomycin in patients with acute bacterial skin and skin structure infections: pooled phase III REVIVE trials (ECCMID 2019) - "Fixed (80mg twice-daily) iclaprim doses had similar efficacy results compared with vancomycin weight/renal function-based dosing across a broad range of lesion sizes in patients treated for ABSSSI in the REVIVE studies."

Clinical • P3 data • Dermatology • Dermatopathology

Iclaprim versus vancomycin for patients with acute bacterial skin and skin structure infection complicated by Staphylococcus aureus or streptococcal bacteraemia: a pooled analysis of the phase III REVIVE trials (ECCMID 2019) - "Among ABSSSI patients with bacteremia, similar proportions of patients treated with iclaprim or vancomycin cleared their bacteremia (83% in each arm, including those with missing cultures). Further study is warranted due to the small number of patients with bacteremia in the REVIVE studies. Table."

P3 data • Retrospective data • Dermatology • Dermatopathology • Diabetes • Metabolic Disorders • DHFR

A pooled analysis of patients with wound infections in the Phase 3 REVIVE trials: randomized, double-blind studies to evaluate the safety and efficacy of iclaprim versus vancomycin for treatment of acute bacterial skin and skin structure infections. (PubMed, J Med Microbiol) - "Based on early clinical response, iclaprim achieved non-inferiority to vancomycin with a similar safety profile in patients with wound infections suspected or confirmed as caused by Gram-positive pathogens. Iclaprim may be a valuable treatment option for wound infections."

Journal • P3 data • Retrospective data • Fatigue

Metformin Protects From Rotenone-Induced Nigrostriatal Neuronal Death in Adult Mice by Activating AMPK-FOXO3 Signaling and Mitigation of Angiogenesis. (PubMed, Front Mol Neurosci) - "In the running study, PD was induced in mice using repeated doses of rotenone and concomitantly treated with MTF 100 or 200 mg/kg/day for 18 days. This study is the first to highlight that the neuroprotective role of MTF is mediated through activation of AMPK-FOXO3 signaling and inhibition of the proangiogenic factor, VEGF. Further studies are warranted to confirm this mechanism in other models of PD and neurodegenerative diseases."

Journal • CNS Disorders • Gene Therapies • Movement Disorders • Parkinson's Disease • CASP3 • FOXO3 • NFE2L2

Pharmacokinetics of iclaprim by age, weight, race and renal/hepatic function in patients with acute bacterial skin and skin structure infections: phase III REVIVE trials (ECCMID 2019) - "In the Phase 3 REVIVE studies, clearance was not impacted by weight, gender, race, renal function or hepatic function. The AUC and Cmax levels in patients ≥65 years old were slightly higher than in younger adults, likely due to slower CL. These differences were not clinically significant and dose adjustment of iclaprim in elderly patients is not warranted."

Clinical • P3 data • PK/PD data • Obesity • DHFR

A Pooled Analysis of the Safety and Efficacy of Iclaprim Versus Vancomycin for the Treatment of Acute Bacterial Skin and Skin Structure Infections in Patients With Intravenous Drug Use: Phase 3 REVIVE Studies. (PubMed, Clin Ther) - "Iclaprim had a higher early clinical response rate and favorable safety profile compared with vancomycin for the treatment of ABSSSIs in patients who were IVDUs. Iclaprim may be a valuable treatment option for ABSSSIs in this patient population."

Journal • P3 data • Retrospective data • Immunology

Molecular Simulation of Oncostatin M and Receptor (OSM-OSMR) Interaction as a Potential Therapeutic Target for Inflammatory Bowel Disease. (PubMed, Front Mol Biosci) - "Based on these important residues, eight residues (OSM: Arg100, Leu103, Phe160, and Gln161; OSMR: Tyr214, Ser223, Asp262, and Trp267) were identified as the "hot spots" through computational alanine mutagenesis analysis and verified by additional MD simulation of R100A (one of the identified "hotspots") mutant. Moreover, six cavities were detected at the OSM-OSMR interface through the FTMap analysis, and they were suggested as important binding sites. The predicted 3D structure of the OSM-OSMR complex and the identified "hot spots" constituting the core of the binding interface provide helpful information in understanding the OSM-OSMR interactions, and the detected sites serve as promising targets in designing small molecules to block the interactions."

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