Interaction with Lipopolysaccharide is Key to Efficacy of Tryptophan- and Arginine-Rich α-Melanocyte-Stimulating Hormone Analogs Against Gram-Negative Bacteria

Article

作者: Patel, Priya ; Mukhopadhyay, Kasturi ; Mondal, Aftab H ; Tiwari, Kanchan

Aim: In order to search for novel antibacterial therapeutics against Gram-negative bacteria, the antibacterial efficacies and mechanism of action of tryptophan- and arginine-rich α-melanocyte-stimulating hormone analogs were investigated. Materials & methods: We performed a killing assay to determine their efficacy; fluorescence, microscopic studies were used to understand their mechanism and peptide–lipopolysaccharide interaction. A checkerboard assay was used to find the effective combination of peptide and antibiotics. Results: Ana-peptides displayed good killing activity against Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. Their strong interaction with lipopolysaccharide damaged the bacterial membranes and led to their subsequent death. Ana-5, the highest cationic and hydrophobic analog, emerged as the most potent peptide, showing synergistic action with rifampicin and erythromycin. Conclusion: Ana-5 can be presented as an important therapeutic candidate against bacterial infections.

2022-12-09·ACS infectious diseases

Efficacy and Toxicity Studies of Novel α-MSH Analogues with Antibiofilm Action and β-Lactam Resensitization Potential against MRSA

Article

作者: Behera, Swastik ; Mukhopadhyay, Kasturi ; Joshi, Seema ; Mumtaz, Sana

Methicillin-resistant Staphylococcus aureus (MRSA), a biofilm-forming recalcitrant pathogen with a multidrug-resistant profile, poses a pandemic threat to human health and is the leading cause of severe infections in both healthcare and community settings. In this study, toward designing novel α-MSH-based peptides with enhanced activity and stability against MRSA, particularly its stationary phase and biofilm, we explored a design approach to augment the hydrophobicity of an 8-mer C-terminal α-MSH(6-13)-based peptide Ana-5 through the incorporation of a bulky unnatural amino acid. The designed Ana-peptides overcame the limitation of diminished activity in biological media and exhibited enhanced antistaphylococcal activity and cell selectivity. With membrane rupture as the primary mode of action, the peptides exhibited inhibitory potential against S. aureus biofilms. Importantly, the peptides did not exhibit any adverse effects in the in vivo toxicity studies and were also able to significantly alleviate bacterial infection in a systemic infection mice model study. Additionally, the peptides retained their activity in the presence of serum and displayed a low propensity toward resistance development in MRSA cells. Moreover, the observed synergistic potential of Ana-10 with conventional antibiotics could be vital in resurrecting discarded antibiotics. Thus, this study provides us with an exciting lead, Ana-10, for further development against biofilm-based chronic S. aureus infections.

2020-02-25·ACS omega3区 · 化学

In Vitro and Ex Vivo Efficacy of Novel Trp-Arg Rich Analogue of α-MSH against Staphylococcus aureus

3区 · 化学

ArticleOA

作者: Mukhopadhyay, Kasturi ; Joshi, Seema ; Singh, Jyotsna ; Mumtaz, Sana

Antimicrobial peptides (AMPs), an essential component of innate immunity, are very important resources for human therapeutics to counter the current threat of drug resistance. We have previously established that one such AMP, α-melanocyte stimulating hormone (α-MSH), an endogenous neuropeptide, and its derivatives have potent antimicrobial activity against Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA). However, the immense potential of α-MSH for therapeutic development against staphylococcal infections is marred by its reduced efficacy in the presence of standard microbiological culture medium. To overcome this issue, in this study, we designed a series of five novel analogues of the C-terminal fragment of α-MSH, i.e., α-MSH(6-13), by replacing uncharged and less hydrophobic residues with tryptophan and arginine to increase the hydrophobicity and cationic charge of the peptide, respectively. While all of the peptides showed a preferential interaction with negatively charged phospholipid vesicles, the most hydrophobic and cationic peptide, i.e., Ana-5, exhibited the highest activity against S. aureus cells while maintaining cell selectivity. Moreover, Ana-5 could retain its activity even in complex media like the Mueller Hinton broth and displayed rapid bactericidal activity in the presence of serum. Ana-5 also caused rapid bacterial membrane depolarization, permeabilization, and cell lysis and was able to bind to polyanionic plasmid DNA suggesting a possible dual mode of action of the peptide. Importantly, Ana-5 was able to eradicate intracellular S. aureus in fibroblast cells similar to conventional antibiotics. Collectively, in the present study, we obtained a potent α-MSH-based analogue with excellent staphylocidal potency in microbial growth medium and ex vivo efficacy, which may translate into therapeutic application.

项与 ANA-5 相关的新闻（医药）

2023-10-12

·BioSpace

Anaconda Biomed Announces Additional Granted Patents for its Innovative Thrombectomy Device for Ischemic Stroke Treatment

BARCELONA--(BUSINESS WIRE)-- Anaconda BioMed S.L, a medical technology company developing next-generation thrombectomy systems, has announced that the European Patent Office has granted the company a European patent for "A Device and a Thrombectomy Apparatus for Extraction of Thrombus from a Blood Vessel," published as Patent No. EP3866708 B1 on September 27, 2023. In addition, the US 11,771,446 B2 was also granted to the company on October 3, 2023, for a method to improve the efficacy of removing cerebral vascular thrombi. The newly granted patents join a list of 17 issued patents for Anaconda Biomed, including “Thrombectomy Device And System For Extraction Of Vascular Thrombi From A Blood Vessel” in the United States with Patent No. US 11,013,523 B2, among other key territories such as recently granted Canada and South Korea, together with Japan, China, Brazil, Taiwan and Australia. The company’s growing patent portfolio demonstrates its dedication to innovation and unwavering mission to revolutionize stroke treatment worldwide. "Every year, approximately 15 million people globally suffer from stroke,” said Richard Ferrari, Anaconda Biomed chairperson. “With these recent achievements, we are one step closer to offering our neurovascular recanalization technology to effectively treat these patients, minimizing death and disabilities, and improving the quality of life for patients and their families." About ANA5 Advanced Neurovascular Access™ ANA5 Advanced Neurovascular Access™ is specifically designed for use in the anterior and posterior neurovascular vessels, including the internal carotid artery (ICA), the M1 and M2 segments of the middle cerebral artery, the basilar artery, the posterior cerebral artery, and the vertebral arteries. ANA5 comprises an aspiration funnel catheter featuring variable stiffness sections to be used in conjunction with a stent retriever. The funnel catheter consists of a radiopaque Nitinol braid covered with a silicone coating to enable local flow restriction. ANA5 is currently an investigational device and is not available for sale in the United States or the European Union. About Anaconda Biomed Anaconda Biomed is an innovative medical technology company dedicated to developing next-generation thrombectomy systems for the treatment of ischemic stroke. At the heart of its product portfolio is the ANA5 Advanced Neurovascular Access™ Thrombectomy Device (ANA5). Anaconda Biomed has received funding from prominent life science investment firms, including Ysios Capital, Omega Funds, Innogest, Asabys Partners, Banco Sabadell, and private investors. Additionally, through public grants, the company has received significant public support from Enisa, CDTI (Neotec), the Ministry of Science & Innovation (Emplea and Retos), EIB, and EIT Health. For more information, please visit

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