SQ-109 / Sequella - LARVOL DELTA

Molecular modelling assisted identification of novel Benzoxazole derivatives as hit molecules targeting Mycobacterial Membrane Protein Large 3 (MmpL3). (PubMed, Comput Biol Med) - "BXZ-IX and BXZ-XIV exhibited potent activity against Mycobacterium smegmatis, with a minimum inhibitory concentration (MIC) of 15.62 μg/mL, compared with SQ109 (standard MmpL3 inhibitor), which had an MIC of 10.0 μg/mL. Overall, ten of the selected benzoxazole compounds significantly inhibited the growth of M. smegmatis, with MICs ranging from 15.62 to 62.5 μg/mL in laboratory tests, demonstrating greater effectiveness against the MmpL3 protein."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • MMP3

Antibiotic dose-response curves can measure antibiotic activity against Mycobacterium abscessus and Mycobacterium peregrinum. (PubMed, bioRxiv) - "We used Clinical and Laboratory Standards Institute growth conditions for rapid-grower nontuberculous mycobacteria to generate 990 dose-response curves across three time points (72 hours, 96 hours, and 120 hours) for six guideline-recommended (clarithromycin, amikacin, cefoxitin, linezolid, tigecycline, and clofazimine) and five new (omadacycline, tedizolid, SPR719, SQ109, and bedaquiline) antibiotics against Mycobacterium abscessus subspecies abscessus ATCC 19977 and Mycobacterium peregrinum ATCC 700686. We identified time-dependent changes in dose-response curve metrics that allow the detection of inducible clarithromycin resistance with only five days of incubation. This study demonstrates the potential of dose-response curves in measuring antibiotic activity against Mycobacterium abscessus ."

Journal • Nontuberculous Mycobacterial Disease • Respiratory Diseases

In vitro and in vivo efficacy of the antimycobacterial molecule SQ109 against the human pathogenic fungus, Cryptococcus neoformans. (PubMed, PLoS Negl Trop Dis) - "Unlike fluconazole (FLC) and flucytosine (5-FC), C. neoformans showed a negligible tendency to develop resistance to SQ109 during frequent passaging. Notably, SQ109 potentiates the activity of the standard antifungal FLC, as well as other ergosterol inhibitors, with a fractional inhibitory concentration Index (ΣFICI) ranging from 0.38 to 1. These findings highlight the therapeutic potential of SQ109 in combating cryptococcal infections, both as a standalone therapy and as an adjuvant to FLC monotherapy."

Journal • Preclinical • Human Immunodeficiency Virus • Infectious Disease • ERG

Activity of Antibacterial/Antifungal Compounds against the Protozoan Parasite, Toxoplasma gondii. (PubMed, ACS Infect Dis) - "This potency was comparable to that observed with the tuberculosis drug candidate SQ109 and a series of its analogs...We also examined correlations between compound activity against the yeast Saccharomyces cerevisiae, and the bacterium Mycobacterium smegmatis, finding significant correlations between the collapse of the proton motive force and antiproliferative activity. Taken together, our findings underscore the potential of these antimicrobial agents as promising leads for the development of new antiparasitic therapies against T. gondii."

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

Microbiological evidence for the trisubstituted benzimidazoles targeting MmpL3 in Mycobacterium tuberculosis. (PubMed, Antimicrob Agents Chemother) - "By using bacterial cytological profiling, we observed that SBZ-treated Mycobacterium tuberculosis cells exhibit cell wall-damaging phenotypes resembling those caused by known cell wall biosynthesis inhibitors, such as AU1235 and SQ109, that mostly target the membrane protein large 3 (MmpL3)...Strains with mutations in mmpL3 exhibited either low- or high-level resistance to the SBZs. A molecule docking model is proposed, based on a high-resolution crystal structure of MmpL3, which could be useful in reconciling the inhibition mechanism and suggesting a further development of MmpL3 inhibitor starting with the SBZ scaffold."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • MMP3

Integration of multi-modal measurements identifies critical mechanisms of tuberculosis drug action. (PubMed, Cell Syst) - "Using morphological data alone with DECIPHAER, we discovered that respiration inhibition by the polypharmacological drugs SQ109 and BM212 can influence cell death more than their effects on the cell wall. This study demonstrates that DECIPHAER can extract the critical shared information from multi-modal measurements to identify cell-death-relevant mechanisms of TB drugs. A record of this paper's transparent peer review process is included in the supplemental information."

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

Structural isomerisation affects the antitubercular activity of adamantyl-isoxyl adducts. (PubMed, J Enzyme Inhib Med Chem) - "SQ109-ISO hybrid compounds were shown to have demonstrable activity against both drug-sensitive and drug-resistant Mtb whilst displaying limited toxicity in vitro in comparison to other antitubercular agents. Indications from our genetic and biochemical studies suggest that these structurally similar pharmacophores bind to different proteins within Mtb, highlighting the need for careful consideration when producing regioisomeric analogues and that the utilisation of previous efficacious structures is a valid approach to developing promising novel drugs against Mtb."

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

Investigating the unbinding mechanisms and kinetics of MmpL3 inhibitors: A computational study. (PubMed, Protein Sci) - "In this study, the τ-random acceleration molecular dynamics (τRAMD) and steered molecular dynamics (SMD) methods were employed to investigate the unbinding mechanisms and kinetics of four representative MmpL3 inhibitors: SQ109, AU1235, NITD349, and BM212...All these inhibitors must traverse the channel formed by Phe255 and Phe644 via the H4H5H10 pathway, necessitating the overcoming of significant energy barriers. Based on these findings, we suggest that enhancing inhibitor interactions with MmpL3, such as through hydrogen bonding or increasing inhibitor size to create larger physical barriers (e.g., interactions with Phe255 and Phe644), may prolong the inhibitors' residence times."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • MMP3

Broad-Spectrum Activity and Mechanisms of Action of SQ109 on a Variety of Fungi. (PubMed, ACS Infect Dis) - "SQ109 disrupted H+/Ca2+ homeostasis in S. cerevisiae vacuoles, and there was synergy (FICI ∼ 0.26) with pitavastatin, indicating involvement of isoprenoid biosynthesis pathway inhibition. SQ109 is, therefore, a potential antifungal agent with multitarget activity."

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

Anti-Parasitics with a Triple Threat: Targeting Parasite Enzymes, the Proton Motive Force, and Host Cell-Mediated Killing. (PubMed, ACS Infect Dis) - "The enhanced activity against intracellular trypanosomatids is seen with Leishmania spp. grown in macrophages but not with Trypanosoma cruzi in epithelial cells and is proposed to be due in part to host-based killing, based on the recent observation that SQ109 is known to convert macrophages to a pro-inflammatory (M1) phenotype."

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

Efficacy of novel regimens targeting oxidative phosphorylation in Mycobacterium tuberculosis. (PubMed, Antimicrob Agents Chemother) - "The combination of bedaquiline, clofazimine, pyrazinamide, alongside telacebec, and SQ109 was investigated against both wild-type M. tuberculosis H37Rv and an Rv0678 mutant with cross-resistance between bedaquiline and clofazimine. The addition of T to BCZ prevented the amplification of bedaquiline-resistant mutants and reduced the number of mice relapsing. Our finding underscores the potential of targeting the OxPhos pathway to combat M. tuberculosis, paving the way for innovative approaches in tuberculosis therapy."

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

Synthesis, Antituberculosis Evaluation and Structure-Activity Relationships of New SQ109 Analogs. (PubMed, Arch Pharm (Weinheim)) - "The SQ109 is a second-generation agent developed from ethambutol that has been emerging as a promising TB agent. The functionalization of its skeleton appears as a strategy to improve the physicochemical and biological properties. Hence, we report the synthesis of functionalized SQ109 scaffolds, the in vitro evaluation against Mycobacterium tuberculosis H37Rv strains, molecular docking simulations, and molecular dynamics of the interactions with the target membrane protein."

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

Exploring spirocyclic isoquinoline-piperidine compounds in tuberculosis therapy: ADMET profiling, docking, DFT, MD simulations, and MMGBSA analysis. (PubMed, Comput Biol Chem) - "This study computationally designed and screened 40 spirocyclic analogs, and compared them with ICA38 and SQ109...Additionally, C21 and C20 maintained Asp645 interactions (91 %, 97 %) and showed strong binding with free energy values (MMGBSA: -72.23, -66.50 kcal/mol). These findings highlight the efficiency of the compounds C21 and C20 with strong binding affinity, favorable stability, and optimal electronic properties, making them promising candidates for further development of next-generation MmpL3 inhibitors."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • MMP3

Characterization of the Orphan Cytochrome P450 CYP135B1 from Mycobacterium tuberculosis: Involvement in Metabolism but Not in the Antibacterial Activity of the Antitubercular Drug SQ109. (PubMed, ACS Infect Dis) - "Notably, CYP135B1 metabolized the anti-TB drug SQ109 by inserting oxygen into its geranyl moiety in a manner distinct from CYP124A1. However, genetic studies using a ΔCYP135B1 mutant strain revealed that CYP135B1 is not required for SQ109's antibacterial activity, as its deletion did not affect drug efficacy despite CYP135B1 metabolizes SQ109."

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

New pyrazole-based derivatives targeting MmpL3 transporter in Mycobacterium tuberculosis: design, synthesis, biological evaluation and molecular docking studies. (PubMed, Mol Divers) - "Interestingly, compounds 15 and 35 were inactive against lab-generated Mtb strains resistant to SQ109, a known MmpL3 inhibitor...This research highlights the potential of pyrazole-based amides as a promising new class of anti-TB drugs. By targeting MmpL3, these compounds offer a novel mechanism of action to combat drug-resistant TB, potentially leading to improved treatment outcomes."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • MMP3

Activity of Carbazole, Aminoguanidine and Diamine Anti-infectives against Toxoplasma gondii. (PubMed, bioRxiv) - "We also tested a series of 18 analogs of the diamine SQ109, a tuberculosis drug candidate which likewise has both antibacterial and antifungal activity, finding activity as low as 2.3 μM. We tested all compounds for their activity in collapsing the ΔpH component of the promotive force, the results indicating that all compounds acted, at least in part, as protonophore uncouplers. Finally, we also investigated the correlation between the activity of all compounds against the yeast Saccharomyces cerevisiae and the bacterium Mycobacterium smegmatis , finding significant correlations between the collapse of the proton motive force and anti- fungal/antibacterial activity."

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

Broad-Spectrum Activity and Mechanisms of Action of SQ109 on a Variety of Fungi. (PubMed, bioRxiv) - "SQ109 disrupted H + /Ca 2+ homeostasis in S. cerevisiae vacuoles, and there was synergy (FICI∼0.31) with pitavastatin, indicating involvement of isoprenoid biosynthesis pathway inhibition. SQ109 is, therefore, a potential antifungal agent with multi-target activity."

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

Mycobactin analogue interacting with siderophore efflux-pump protein: insights from molecular dynamics simulations and whole-cell assays. (PubMed, Front Antibiot) - "In recent decades, notable approaches have been accounted for EPI development and have resulted in the discovery of several EPIs including SQ109 and AU1235. Compound Il with bedaquiline highlighted an additive profile against the M. abscessus pathogen. MD simulations and whole-cell assays are indicating potential development of compound Il as an adjunct to the existing therapeutic regimen against mycobacterial infections."

Journal • Infectious Disease

Targeting the Heart of Mycobacterium: Advances in Anti-Tubercular Agents Disrupting Cell Wall Biosynthesis. (PubMed, Pharmaceuticals (Basel)) - "Isoniazid, thioamides, and delamanid primarily disrupt mycolic acid synthesis, with recent evidence indicating that delamanid also inhibits decaprenylphosphoryl-β-D-ribose-2-epimerase, thereby impairing arabinogalactan biosynthesis. Furthermore, ethambutol interferes with arabinogalactan synthesis by targeting arabinosyl transferase enzymes, particularly embB- and embC-encoded variants. Beyond these, six promising molecules currently in Phase II clinical trials are designed to target arabinan synthesis pathways, sutezolid, TBA 7371, OPC-167832, SQ109, and both benzothiazinone derivatives BTZ043 and PBTZ169, highlighting advancements in the development of cell wall-targeting therapies."

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

Deciphering the possible role of MmpL7 efflux pump in SQ109 resistance in Mycobacterium tuberculosis. (PubMed, Ann Clin Microbiol Antimicrob) - "Our data demonstrated that SQ109 exhibited excellent levels of in vitro activity against MTB. MmpL7 may be a potential gene for MTB resistance to SQ109, providing a useful target for detecting SQ109 resistance in MTB."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • MMP3 • MMP7

Repurposing antiparasitic N,N'-aliphatic diamine derivatives as promising antimycobacterial agents. (PubMed, Arch Pharm (Weinheim)) - "Considering the structure similarity between this collection and SQ109, an antituberculosis compound, and its compelling antiparasitic properties, we aimed to repurpose this library for tuberculosis treatment...Nevertheless, none of the compounds displayed experimental inhibition. In summary, our study confirms the validity of the repurposing approach and underscores the antimycobacterial potential of NNDDA compounds, especially the analog 3c, setting a stepping stone for further studies."

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

Allosteric coupling of substrate binding and proton translocation in MmpL3 transporter from Mycobacterium tuberculosis. (PubMed, mBio) - "The lipid extraction activity was modulated by substitutions in critical charged and polar residues of the periplasmic substrate-binding pocket of MmpL3, coupled to the proton transfer activity of MmpL3 and inhibited by a small molecule inhibitor SQ109...We further uncovered the mechanism of how the binding of a substrate in the periplasmic domain is communicated to the transmembrane proton relay of MmpL3. The uncovered mechanism and the developed assays provide new opportunities for mechanistic analyses of MmpL3 function and its inhibition."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • MMP3

The Tuberculosis Drug Candidate SQ109 and Its Analogs Have Multistage Activity against Plasmodium falciparum. (PubMed, ACS Infect Dis) - "Frontrunner compounds showed conserved activity against genetically diverse southern African clinical isolates. We additionally validated that this series could block transmission to mosquitoes, marking these compounds as novel chemotypes with multistage antiplasmodial activity."

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

SQ109, a Novel Clinical-Stage Drug, Used to Treat Murine Cutaneous Leishmania major Infection (ASM Microbe 2024) - "SQ109 is a novel lipophilic small molecule, [1,2]-ethylenediamine structure of ethambutol (Protopopova M JAC 2005). Infection Outcomes by Treatment Group at Day 16 Post InitiationTest (units)No TreatmentSQ109Liposomal AmphotericinIVIS (total flux p/s) median, range9 E06 (4-690 E06)26 E06 (10-93 E06)4.58 E05 (0-28.8 E05)Evolution Index (ear induration)0.80.70.4Limiting Dilution Assay (parasite/gram tissue)4.44 E054.58 E055.0 E03Quantitative PCR (DNA copies/mL)4.5 E043.9 E041.09 E03In conclusion in this BALB/c mouse CL model, treatment with a dose of 10mg/kg/day SQ109 IP for 14 doses did not show efficacy in the treatment of L. major. Toxicity may limit any additional increase in daily dose although a longer duration of therapy could be tested further since steady state is slow to develop with SQ109."

Preclinical • Dermatology • Infectious Disease

Novel Inhibitors to MmpL3 Transporter of Mycobacterium tuberculosis by Structure-Based High-Throughput Virtual Screening and Molecular Dynamics Simulations. (PubMed, ACS Omega) - "From this, the top nine compounds and the MmpL3-SQ109 crystal complex structure each underwent 2 × 200 ns MD simulations to probe the inhibitor binding energetics to MmpL3. Four of the nine compounds exhibited stable binding properties and favorable drug properties, suggesting these four compounds could be potential novel inhibitors of MmpL3 for M. tuberculosis."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • MMP3