Voxvoganan trihydrochloride targets the bacterial cell membrane. As a synthetic antimicrobial peptidomimetic (SAMP), it mimics the mechanism of action of host defense peptides (e.g., defensins and cathelicidins) without being susceptible to proteolytic degradation. The compound binds to negatively charged components of the bacterial cell wall and membrane (such as lipoteichoic acid in Gram-positive bacteria and lipopolysaccharide in Gram-negative bacteria) via electrostatic interactions. Once bound, voxvoganan inserts into the membrane, disrupting its integrity, causing membrane depolarization, increasing permeability, and ultimately leading to cell lysis and bacterial death. This mechanism of action is rapid and bactericidal, reducing the likelihood of resistance development, as it is not dependent on specific intracellular targets. The compound acts in a sphingolipid-dependent manner, disrupting plasma membrane integrity. Due to its broad-spectrum activity and rapid killing, voxvoganan is effective against both dividing and non-dividing bacteria, as well as against biofilms. Selectivity for bacterial membranes (which contain negatively charged phospholipids) over mammalian cell membranes (which have a zwitterionic outer leaflet) accounts for its low mammalian cytotoxicity.

Voxvoganan trihydrochloride (LTX-109), is an experimental antimicrobial drug studied with a membrane-lysing mode of action based on the biological theory of innate immune effectors. Its bactericidal lytic action is quick with voxvoganan trihydrochloride. Several S. species are susceptible to the bactericidal effects of voxvoganan trihydrochloride in vitro. antimicrobial agent classes that this investigation investigated were resistant to aureus isolates[2]. Being a broad-spectrum, fast-acting bactericidal antimicrobial drug, loxvoganan trihydrochloride (LTX-109), causes membrane breakdown and cell lysis by binding to negatively charged membrane components on the bacterial cell wall. One of a kind tiny peptide medication that is resistant to protease degradation is voxvoganan trihydrochloride, which is chemically produced. Applying Voxvoganan trihydrochloride topically has a poor bioavailability and an excellent safety profile. Relatively effective against isolates of Staphylococcus aureus that are both susceptible and resistant to mupirocin is voxvoganan trihydrochloride[3].

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In vitro antimicrobial susceptibility testing has demonstrated that voxvoganan trihydrochloride is highly effective against S. aureus, including MRSA, with an MIC range of 2-4 ug/mL. It exhibits rapid bactericidal activity, achieving a ≥3 log10 reduction in bacterial counts within 30-60 min of exposure. The compound also shows activity against other Gram-positive bacteria, including coagulase-negative staphylococci, Streptococcus pyogenes, Enterococcus faecalis, and against some Gram-negative bacteria (e.g., Escherichia coli, Pseudomonas aeruginosa) at higher concentrations (MIC 4-32 ug/mL). Voxvoganan also possesses fungicidal activity against Candida albicans and other Candida species. In time-kill assays, it demonstrates concentration-dependent killing, with no significant regrowth observed over 24 h. The compound has a low propensity for resistance development; serial passage of S. aureus in subinhibitory concentrations for 15 days did not result in a significant increase in MIC. In vitro cytotoxicity assays using human skin fibroblasts, keratinocytes, or other mammalian cell lines show that voxvoganan has a favorable selectivity index, with therapeutic concentrations (2-8 ug/mL) well below the CC₅0 (50% cytotoxic concentration, typically >200 ug/mL). It also demonstrates activity against biofilms formed by S. aureus. The compound retains activity under physiological conditions (e.g., presence of serum, pH variation), making it suitable for topical application.

In vivo efficacy of voxvoganan trihydrochloride has been evaluated in animal models of skin infection and nasal decolonization. In a mouse model of superficial skin infection (e.g., S. aureus or MRSA), topical application of voxvoganan (0.5-2% w/w cream or ointment) once or twice daily for 3-5 days significantly reduces bacterial burden in the skin compared to vehicle controls, with efficacy comparable to mupirocin or fusidic acid (standard topical antibiotics). In a mouse model of nasal decolonization (S. aureus colonization of the nares), intranasal administration of voxvoganan reduces the bacterial load, supporting its potential use for reducing MRSA carriage. The compound is generally well tolerated, with no significant skin irritation or systemic toxicity observed in these models. Voxvoganan has been evaluated in Phase II clinical trials (clinicaltrials.gov identifiers not publicly disclosed) for the topical treatment of uncomplicated skin and soft tissue infections (e.g., impetigo) and for the eradication of nasal MRSA carriage. The clinical development of LTX-109 (voxvoganan) has progressed to Phase II, but further updates may be pending. The compound is not yet approved for human use.

A standard non-cellular assay for voxvoganan trihydrochloride is the measurement of its membrane-disrupting activity using artificial lipid vesicles (liposomes) or bacterial membrane preparations. For membrane disruption assays: large unilamellar vesicles (LUVs) composed of phosphatidylcholine (PC) and phosphatidylglycerol (PG) (e.g., 3:1 ratio to mimic bacterial membrane composition) are prepared by lipid film hydration and extrusion. A fluorescent dye (e.g., calcein at 50-100 mM self-quenching concentration) is encapsulated in the liposomes during preparation. Voxvoganan trihydrochloride at varying concentrations (0.5-128 ug/mL) is added to the liposome suspension. Membrane disruption causes leakage of calcein, which dilutes into the medium, resulting in an increase in fluorescence (excitation 485 nm, emission 535 nm). The percentage of leakage is calculated relative to 100% leakage achieved by Triton X-100 (1%). Alternatively, a bacterial membrane preparation (e.g., isolated from S. aureus) can be used to measure the dissipation of membrane potential using a voltage-sensitive fluorescent dye such as DiSC3(5) (3,3′-dipropylthiadicarbocyanine iodide). A reduction in fluorescence indicates membrane depolarization. These assays confirm the membrane-lysing mechanism. IC₅0 values for membrane disruption are typically in the low ug/mL range.

In vitro cell-based assays for voxvoganan trihydrochloride are performed using broth microdilution methods according to CLSI guidelines. Bacterial strains (e.g., S. aureus ATCC 29213, MRSA clinical isolates) are cultured overnight in cation-adjusted Mueller-Hinton broth (MHB) at 37degC. The bacterial suspension is adjusted to 0.5 McFarland standard (~1-2 × 10⁸ CFU/mL) and diluted 1:100 in MHB to a final inoculum of approximately 5 × 10⁵ CFU/well in 96-well plates. Voxvoganan is serially diluted two-fold (0.125-256 ug/mL). Plates are incubated at 37degC for 16-20 h. MIC is defined as the lowest concentration that completely inhibits visible growth (measured spectrophotometrically at 600 nm or by visual inspection). For time-kill kinetics, bacterial cultures (~10⁶ CFU/mL) are treated with voxvoganan at 1×, 2×, 4×, and 8× MIC, and aliquots are plated at 0, 0.5, 1, 2, 4, 6, 8, and 24 h for CFU enumeration. For cytotoxicity studies, human skin fibroblasts (HSF) or keratinocytes (HaCaT) are cultured in DMEM + 10% FBS at 37degC in 5% CO2. Cells are seeded in 96-well plates at 1 × 10⁴ cells/well, treated with voxvoganan (0-500 ug/mL) for 24-48 h, and cell viability is measured using MTT assay (0.5 mg/mL, 4 h, absorbance at 570 nm) or CellTiter-Glo. The CC₅0 (50% cytotoxic concentration) is typically >200 ug/mL, indicating a high therapeutic index (CC₅0/MIC >50).

In vivo animal studies for voxvoganan trihydrochloride are performed in female BALB/c mice (6-8 weeks old, 18-22 g) for skin infection models. The back skin of the mice is shaved and depilated, and the skin is tape-stripped to create minor abrasion. An inoculum of 1 × 10⁷-1 × 10⁸ CFU of S. aureus or MRSA is applied topically to the abraded skin and allowed to establish infection for 2-4 h. After infection, mice are randomized into treatment groups (n = 6-10 per group). Voxvoganan is formulated as a cream or ointment (0.5%, 1%, or 2% w/w) and applied topically to the infected area once or twice daily for 3-5 days. Control groups receive vehicle base or a comparator topical antibiotic (e.g., mupirocin 2% cream). After the treatment period, mice are euthanized, and a punch biopsy (6-8 mm) of the infected skin is taken. The skin sample is homogenized in sterile PBS, and serial dilutions are plated onto tryptic soy agar to enumerate CFU per gram of tissue. The reduction in bacterial burden (log10 CFU/g) relative to the vehicle control is calculated. For nasal decolonization models, S. aureus is inoculated intranasally (10 uL suspension, 1 × 10⁷ CFU) into anesthetized mice. Voxvoganan (in an intranasal formulation) is administered via nasal drops, and bacterial counts in nasal washes are measured. In all studies, skin irritation is assessed by a visual score (erythema, edema) and histopathology of skin sections (H&E staining). All animal procedures must be approved by the institutional animal care and use committee.

The pharmacokinetic (PK) properties of voxvoganan trihydrochloride are relevant for its intended topical application, where systemic absorption is minimal. In animal studies, topical application of the compound results in very low or undetectable systemic exposure, as the compound is largely retained in the skin. The drug is not intended for oral or parenteral administration. For clinical development, the compound is formulated as a topical cream, ointment, or gel for local application, and systemic absorption is expected to be negligible due to the compound's high molecular weight (~1300-1500 g/mol for the trihydrochloride salt) and cationic amphiphilic structure, which limits penetration through intact skin. Minimal systemic exposure reduces the risk of off-target toxicity. No detailed human PK data are publicly available, but given the Phase II clinical development, such data exist but are not disclosed. Voxvoganan is for topical use only; not for systemic administration.

Toxicological data for voxvoganan trihydrochloride have been assessed in preclinical studies as part of its development program. In animal studies (mice, rats), topical application of voxvoganan at concentrations up to 2% w/w for up to 28 days resulted in no significant systemic toxicity, and no skin sensitization or significant irritation was observed. In vitro cytotoxicity assays using human skin fibroblasts and keratinocytes show a CC₅0 typically >200 ug/mL, indicating low mammalian cell toxicity. No genotoxicity has been reported (Ames test negative). Reproductive and developmental toxicity studies have not been disclosed. The compound is generally well tolerated at topical therapeutic doses. Systemic exposure is negligible due to limited absorption through intact skin. For reference only; not for human use outside clinical trial settings.

[1]. Johan Isaksson, et al. A synthetic antimicrobial peptidomimetic (LTX 109): stereochemical impact on membrane disruption. J Med Chem. 2011 Aug 25;54(16):5786-95.
[2]. Louis D Saravolatz, et al. In vitro activities of LTX-109, a synthetic antimicrobial peptide, against methicillin-resistant, vancomycin-intermediate, vancomycin-resistant, daptomycin-nonsusceptible, and linezolid-nonsusceptible Staphylococcus aureus. Antimicrob Agents Chemother. 2012 Aug;56(8):4478-82.
[3]. L D Saravolatz, et al. Postantibiotic effect and postantibiotic sub-MIC effect of LTX-109 and mupirocin on Staphylococcus aureus blood isolates. Lett Appl Microbiol. 2017 Nov;65(5):410-413.

Voxvoganan trihydrochloride (LTX-109) is an investigational topical antimicrobial drug candidate that has completed Phase II clinical trials. It is not yet approved for human use. The mechanism of action is rapid membrane disruption and cell lysis via binding to negatively charged bacterial membrane components, similar to host defense peptides. Voxvoganan is broad-spectrum, fast-acting, bactericidal, and fungicidal, with a low propensity for resistance development. It is being developed for the topical treatment of skin and soft tissue infections (e.g., impetigo, infected dermatitis) and for the eradication of nasal MRSA carriage. Clinical trial results have been reported, but the compound is not yet commercially available. For research use only; reference standard for non-clinical applications.

C43H72CL3N11O3

Typically exists as solid at room temperature

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO :~140 mg/mL (~156.00 mM)

Solubility in Formulation 1: ≥ 3.5 mg/mL (3.90 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 35.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 3.5 mg/mL (3.90 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 35.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 3.5 mg/mL (3.90 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 35.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)