Locilex (pexiganan acetate) / PLx Pharma - LARVOL DELTA

Vm-MSI: a Vancomycin-Antimicrobial Peptide Conjugate Combating Resistant Bacteria and Broadening the Antimicrobial Spectrum. (PubMed, Adv Sci (Weinh)) - "Among the acquired conjugates, Vm-MSI showed a 20.18 fold improvement in antimicrobial activity over vancomycin and a 1.95 fold increase compared to the parent peptide MSI-78. In vivo, Vm-MSI displayed remarkable therapeutic efficacy in mouse models of VRSA-induced skin infection and multidrug-resistant A. baumannii-induced lung infection. These findings underscore the great potential of Vm-MSI as an effective treatment for infections caused by vancomycin-resistant and Gram-negative bacteria."

Journal • Dermatology • Infectious Disease • Respiratory Diseases

Peptide-based antibiotics: structure-driven strategies to tackle toxicity and resistance of antimicrobial peptides. (PubMed, Bioorg Med Chem) - "This review focuses on five representative AMPs: daptomycin, pexiganan (MSI-78), murepavadin (POL7080), iseganan (IB-367), and omiganan (MBI-226), and involves an analysis of their clinical development, mechanisms of resistance, toxicity profiles, and resultant outcomes. Furthermore, we discuss prospective peptide design strategies that may effectively address these challenges. Notably, we underscore the potential of structure-based strategies, including amino acid substitutions and conjugation with diverse molecular entities (such as small functional groups, synthetic polymers, peptides, and antibiotics), as promising pathways to mitigate these barriers and advance the development of clinically viable AMP therapeutics."

Journal • Review

AI-guided discovery and optimization of antimicrobial peptides through species-aware language model. (PubMed, Brief Bioinform) - "Notably, peptides 13-5 and 16 demonstrated antimicrobial potency and selectivity comparable to the clinically investigated AMP pexiganan. Our work demonstrates the potential of AI to expedite the discovery of peptide-based antibiotics to combat antibiotic resistance."

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Neutron reflectometry reveals conformational changes in a mechanosensitive protein induced by an antimicrobial peptide in tethered lipid bilayers. (PubMed, J Colloid Interface Sci) - "Addition of 1.6 and 3.2 μM pexiganan resulted in a decrease in the protrusion of MscL (from ∼46 to ∼38 Å). To our knowledge, these findings represent the first direct experimental evidence of a structural change in the C-terminus containing protrusion of MscL, triggered by an antimicrobial peptide."

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Uncovering the genetic basis of Staphylococcus aureus resistance to single antimicrobial peptides and their combinations. (PubMed, iScience) - "Here, we investigated the genetic mechanisms of resistance evolution in Staphylococcus aureus against single and combined AMPs (temporin, melittin, and pexiganan)...The findings suggest that AMP combinations might limit mutation accumulation, while constraining the development of general AMP resistance. The genetic mechanism of resistance is complex, thus careful selection is required for designing effective AMP-based therapies."

Journal

Generation of VacA-targeting guide peptides to increase specific antimicrobial peptide toxicity against Helicobacter pylori. (PubMed, J Biotechnol) - "Guide peptide biopanning provides an effective, scalable method to increase specific activity of antimicrobial peptides based on attraction to a key virulence factor."

Journal • Gastric Cancer • Infectious Disease • Oncology • Solid Tumor

Charge, Hydrophobicity, and Lipid Type Drive Antimicrobial Peptides' Unique Perturbation Ensembles. (PubMed, Biochemistry) - "The membrane curvature changes induced by pexiganan relative to magainin suggest that AMPs with larger charges have more potential in modulating bilayer bending. These insights advance our understanding of AMP-membrane interactions at the molecular level, offering guidance for the design of targeted antimicrobial therapies."

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The discovery of novel antimicrobial peptides against drug-resistant bacteria based on fragments fusion strategy. (PubMed, Eur J Med Chem) - "This study designed a series of antimicrobial peptides by fusing two fragments of antimicrobial peptides sC184b (1-9) and MSI-78 (10-16)...Moreover, 13DKallDab displayed low cytotoxicity and hemolysis in vitro, and significant therapeutic efficacy in a mouse acute peritonitis model. These findings demonstrate that 13DKallDab is a promising antimicrobial agent in counteracting multidrug-resistant bacterial infections."

Journal • Hematological Disorders • Infectious Disease

Evolutionary trajectory of bacterial resistance to antibiotics and antimicrobial peptides in Escherichia coli. (PubMed, mSystems) - "We reveal that E. coli develops resistance to antibiotics, particularly ciprofloxacin and kanamycin, at a notably faster rate than to AMPs...Notably, we demonstrate that trimethoprim-resistant E. coli, with mutations in thyA gene, displays enhanced susceptibility to pexiganan, as evidenced by both in vitro and in vivo studies...Additionally, these antibiotic-resistant strains incur significant fitness costs, particularly in bacterial growth and motility. Most importantly, we find that some antibiotic-resistant strains show collateral sensitivity to specific AMPs in both in vitro and animal infection models, which is conducive to accelerating the development of AMP-based antibacterial treatment."

Journal • Infectious Disease

Assessment of Linear and Cyclic Peptides' Immobilization onto Cross-Linked, Poly(vinyl alcohol)/Cellulose Nanocrystal Nanofibers Electrospun over Quartz Crystal Microbalances with Dissipation Sensors. (PubMed, Langmuir) - "This study aims at exploring for the first time the influence of electrospun poly(vinyl alcohol)-based nanofibers on the adsorption of a cyclic peptide, Tiger 17, and of a linear peptide, Pexiganan, using quartz crystal microbalance with dissipation monitoring (QCM-D)...Elastic shear modulus data on this peptide sequence, over the C80/20 electrospun mats, reported 220 and 249 kPa for each peptide, respectively, indicating the formation of stable bonds with the surface. The results contributed to the understanding of the immobilization of linear and cyclic peptides, never studied in combination, and their mutual influence on polymeric substrates for engineering potential wound treatment strategies."

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Dhvar5- and MSI78-coated titanium are bactericidal against methicillin-resistant Staphylococcus aureus, immunomodulatory and osteogenic. (PubMed, Acta Biomater) - "The developed coatings displayed MRSA-sterilizing activity, while revealing an immunomodulatory potential towards macrophages and promoting osteoblastic cell differentiation. This strategy allows a quick and easy immobilization of high quantities of AMP, unlike most other approaches, thus favoring its clinical translation."

Immunomodulating • Journal • Immunology • Infectious Disease • Orthopedics • CCR7 • CD163 • IFNG • IL6 • TNFA

Understanding Antimicrobial Peptide Synergy: Differential Binding Interactions and Their Impact on Membrane Integrity. (PubMed, J Phys Chem B) - "In this study, we conducted molecular dynamics simulations for two heterogeneous aggregates of melittin-indolicidin and pexiganan-indolicidin to observe their structures in the solution phase and their interactions with the lipid membrane...We also found that the amino acid residues forming the surface of the AMP aggregate show differential binding strengths to different lipid species forming the lipid membrane, thereby disrupting the membrane in a way that weakens its integrity. Through this, we provided insight into the basic principle of how the synergistic effect of AMPs occurs."

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Evaluation of the activity of antimicrobial peptides against bacterial vaginosis. (PubMed, Open Life Sci) - "The results showed that Pexiganan, melittin, and cathelicidin-DM had significant antibacterial activity against both Gram-negative and Gram-positive bacteria. AMPs have great potential for clinical application in the treatment of vaginitis, and this study provides an experimental basis for their use in the active immunoprophylaxis of BV."

Journal • Gynecology • Infectious Disease • Vaginitis

Testing Synergy of Highly Selective Antimicrobial Peptides Targeting Different Virulence Factors of Helicobacter pylori (ASM Microbe 2024) - "Next, each guide candidate will be added to the AMP, pexiganan...These gAMPs will then be used in combination with gAMPs already produced which target VacA to examine synergistic toxicity against H. pylori. Every combination of anti-CagA gAMP with anti-VacA gAMP will be tested to determine if synergy is possible by assaying for toxicity against H. pylori."

Gastric Cancer • Gastrointestinal Cancer • Infectious Disease • Oncology • Solid Tumor • KEAP1

Sustain-release lipid-liquid crystal formulations of pexiganan against Helicobacter pylori infection: in vitro evaluation in C57BL/6 mice. (PubMed, BMC Pharmacol Toxicol) - "Clarithromycin was more effective than pexiganan at all tested concentrations. Furthermore, the pexiganan-loaded LLCs exhibited superior efficacy in curing H. pylori infection in a mouse model compared to pexiganan alone. This formulation can enhance H. pylori clearance while mitigating the adverse effects, typically associated with conventional drugs, leading to a viable alternative to current treatment options."

Journal • Preclinical • Gastroenterology • Gastrointestinal Disorder • Infectious Disease

Absence of Synergism between a Dual-AMP Biogel and Antibiotics Used as Therapeutic Agents for Diabetic Foot Infections. (PubMed, Int J Mol Sci) - "Pexiganan and nisin A are antimicrobial peptides (AMPs), and their application may complement conventional antibiotics in DFI treatment. Our main conclusion was that the dual-AMP biogel combined with gentamicin, clindamycin, or vancomycin was not able to significantly reduce bacterial growth or eradicate S. aureus and P. aeruginosa DFI isolates. We further reported an antagonism between dual-AMP and dual-AMP combined with antibiotics against S. aureus."

Journal • Infectious Disease

Novel anti-microbial peptides derived from differentiating adipose-derived stem cells against chronic wound infections (WCD 2023) - P3 | "Activated ASC-CM exhibited significant bacterial killing and antibiofilm effects against vancomycin-resistant Enterococcus faecalis, MDR Pseudomonas aeruginosa and methicillin resistant Staphylococcus aureus (MRSA). First, we identified two potent, non-toxic, novel AMPs, and discovered ultra-short regions (>22-residues) within the AMPs exhibiting enhanced antimicrobial efficacy, prevention acquisition of AMR, improved migration of human keratinocytes, reduced cytotoxicity and hemolysis compared to pexiganan (Phase III clinical trial AMP, NCT01590758) and most antibiotics commonly prescribed for chronic wound management. We aim to develop our lead preclinical peptide into a clinical candidate for the treatment of chronic wound infections. Successful outcome of our proposal has a potential to be translated to a phase I clinical trial against wound infection in particular chronic wound management"

Diabetes • Hematological Disorders • Infectious Disease • Metabolic Disorders

Strategies adopted by gastric pathogen Helicobacter pylori for a mature biofilm formation: Antimicrobial peptides as a visionary treatment. (PubMed, Microbiol Res) - "To our knowledge, this review is the first of its kind to explain briefly the journey of H. pylori starting with the chemotaxis, the mechanism for selecting the site for colonization, the stress faced by the pathogen, and various adaptations to evade these stress conditions by forming biofilm and the morphological changes acquired by the pathogen in mature biofilm. Furthermore, we have explained the human GI tract antimicrobial peptides and the reason behind the failure of these AMPs, and how encapsulation of Pexiganan-A(MSI-78A) in a chitosan microsphere increases the efficiency of eradication."

Journal • Review • Gastrointestinal Disorder • Infectious Disease

Interaction of Pexiganan (MSI-78)-Derived Analogues Reduces Inflammation and TLR4-Mediated Cytokine Secretion: A Comparative Study. (PubMed, ACS Omega) - "Two new AMPs, MSI-Seg-F2F and MSI-N7K, preserved their neutralizing endotoxin activity while reducing toxicity and hemolytic activity. Combining all of these properties makes the designed peptides potential candidates to eradicate bacterial infection and detoxify LPS, which might be useful for sepsis treatment."

Journal • Infectious Disease • Inflammation • Septic Shock • TLR4

A BIOMATERIAL APPROACH BASED ON CHITOSAN NANOPARTICLES FUNCTIONALIZED WITH ANTIMICROBIAL PEPTIDES: THE LAST PIECE IN THE PUZZLE AGAINST HELICOBACTER PYLORI (DDW 2023) - "Among the few AMPs reported to have activity against H. pylori , MSI-78A (PexigananA) is the more promising one 5...137:186-198, 2022;5.Parreira et al. Sci Rep 9, 18212, 2019"

Gastric Adenocarcinoma • Gastric Cancer • Gastrointestinal Cancer • Infectious Disease • Oncology • Solid Tumor

Peptide Flexibility and the Hydrophobic Moment are Determinants to Evaluate the Clinical Potential of Magainins. (PubMed, J Membr Biol) - "The flexibility of another magainin analog (MSI-78) is even greater than that of Mag-2...Such characteristics are key to understanding the broad-spectrum antimicrobial actions exhibited by this peptide. These data reinforce the hypothesis on the determinant role of spontaneous membrane curvature, intrinsic peptide flexibility, and specific hydrophobic moment in assessing the bioactivity of membrane-active antimicrobial peptides."

Journal • Targeted Protein Degradation

Role of lipopolysaccharide in antimicrobial and cell penetrating peptide membrane interactions probed by deuterium NMR of whole cells. (PubMed, BBA Adv) - "Surprisingly, we also found that at the level of H_NMR, the peptide-induced acyl chain disruption is similar for MSI-78 and TP2, although MSI-78 permeabilizes the bilayer and TP2 does not. Furthermore, LPS disruption appears to protect the bacteria from TP2, although it sensitizes them to MSI-78."

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The Impact of Antimicrobial Peptides on the Acinetobacter baumannii Inner Membrane Is Modulated by Lipid Polyunsaturation. (PubMed, ACS Infect Dis) - "Using coarse-grained molecular dynamics simulations of complex A. baumannii inner membrane models derived from lipidomes of bacteria grown in the presence and absence of PUFAs, we examine the impact of the adsorption of four prototypical AMPs (CAMEL, LL-37, pexiganan, and magainin-2) on the membrane biophysical properties...The changes to the membrane biophysical properties also showed a complex relationship with the AMP's physical properties, such as AMP charge, chain length, and charge-to-mass ratio. Cumulatively, this work highlights the importance of studying AMPs using a complex membrane environment and provides insights into the mechanistic action of AMPs in polyunsaturated lipid-rich bacterial membranes."

Journal • Infectious Disease

The role of hydrophobic patches of de novo designed MSI-78 and VG16KRKP antimicrobial peptides on fragmenting model bilayer membranes. (PubMed, Biophys Chem) - "Furthermore, we anticipate the designed AMPs follow the carpet and toroidal pore mechanisms when lysing the cell membrane. This study highlights the significance of the effect of the overall charges and the hydrophobicity of the novel AMPs designed for antimicrobial activity."

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Rational design of stapled antimicrobial peptides. (PubMed, Amino Acids) - P3 | "Antimicrobial peptides under clinical trial: Pexiganan (NCT01594762, 2012-05-07). Omiganan (NCT02576847, 2015-10-13)."

Journal • Review • Infectious Disease