Engineered Cationic Antibiotic peptides

Edeines, a group of cationic antimicrobial peptides produced by the soil bacterium Brevibacillus, have broad biological effects, such as antimicrobial, anticancer and immunosuppressive activities. However, the yield of edeines in wild-type (WT) Brevibacillus is extremely low, and chemical synthesis of edeines is a time-consuming process. Genetic engineering has proven to be an effective approach to produce antibiotics with high yield. In this study, the edeine biosynthetic gene cluster (ede BGC), which is involved in edeine production, was identified and characterized in Brevibacillus brevis X23...

Antibiotic resistance is a significant threat to human health, with natural products remaining the best source for new antimicrobial compounds. Antimicrobial peptides (AMPs) are natural products with great potential for clinical use as they are small, amenable to customization, and show broad-spectrum activities. Lynronne-1 is a promising AMP identified in the rumen microbiome that shows broad-spectrum activity against pathogens such as methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii...

BACKGROUND: The concern regarding a post-antibiotic era with increasing drug resistance by pathogens imposes the need to discover alternatives for existing antibiotics. Antimicrobial peptides (AMPs) with their versatile therapeutic properties are a group of promising molecules with curative potentials. These evolutionarily conserved molecules play important roles in the innate immune system of several organisms. The β-defensins are a group of cysteine rich cationic antimicrobial peptides that play an important role in the innate immune system by their antimicrobial activity against the invading pathogens...

The drug-impermeable bacterial membrane in Gram-negative pathogens limits antibiotic access to intracellular drug targets. To expand our rapidly waning antibiotic arsenal, one approach is to improve the intracellular delivery of drugs with historically poor accumulation in Gram-negative bacteria. To do so, we engineered macromolecular potentiators to permeabilize the Gram-negative membrane to facilitate drug influx. Potentiators, known as WD40, were synthesized by grafting multiple copies of a cationic α-helical antimicrobial peptide, WLBU2, onto a dextran polymer scaffold...

Photodynamic therapy (PDT), an emerging approach that involves photosensitizers, light, and molecular oxygen, has shown promise for fighting periodontitis. However, PDT does not always acquire the desired therapeutic outcomes since some photosensitizers have strong hydrophobic properties and are difficult to absorb efficiently by periodontal pathogenic bacteria. Here, a hydrophobic photosensitizer chlorin e6 (Ce6) was hydrophilically modified via conjugation with TAT peptide, a cationic cell-penetrating peptide, to improve its solubility and enhance its bacterial adsorption by promoting its interaction with the negatively charged cell walls and penetration through the cell membranes...

Insertion of a central venous catheter is one of the most common invasive procedures applied in hemodialysis therapy for end-stage renal disease. The most important complication of a central venous catheter is catheter-related infections that increase hospitalization and duration of intensive care unit stay, cost of treatment, mortality, and morbidity rates. Pathogenic microorganisms, such as, bacteria and fungi, enter the body from the catheter insertion site and the surface of the catheter can become colonized...

The increasing rate of antibiotic resistance constitutes a global health crisis. Antimicrobial peptides (AMPs) have the property to selectively kill bacteria regardless of resistance to traditional antibiotics. However, several challenges (e.g., reduced activity in the presence of serum and lack of efficacy in vivo) to clinical development need to be overcome. In the last two decades, we have addressed many of those challenges by engineering cationic AMPs de novo for optimization under test conditions that typically inhibit the activities of natural AMPs, including systemic efficacy...

Periprosthetic joint infection of total knee arthroplasties represents a major challenge to the field of orthopedic surgery. These infections are commonly associated with antibiotic-tolerant Staphylococcus aureus biofilms. Engineered cationic amphipathic peptide WLBU2 has shown the ability to kill antibiotic-resistant pathogens and drug-tolerant bacterial biofilms. The novelty of using WLBU2 during the direct irrigation and debridement of periprosthetic joint infections led our group to investigate the optimal washout conditions for treatment of S...

The rising prevalence of antibiotic resistance underscores the urgent need for novel antimicrobial agents. Antimicrobial peptides (AMPs) are potentially effective therapeutics that disrupt bacterial membranes regardless of resistance to traditional antibiotics. We have developed engineered cationic AMPs (eCAPs) with broad activity against multidrug-resistant (MDR) bacteria, but stability remains an important concern. Therefore, we sought to enhance the clinical utility of eCAP WLBU2 in biological matrices relevant to respiratory infection...

Staphylococcus aureus is notoriously known for its rapid development of resistance to conventional antibiotics. S. aureus can alter its membrane composition to reduce the killing effect of antibiotics and antimicrobial peptides (AMPs). To obtain a more complete picture, this study identified the resistance genes of S. aureus in response to human cathelicidin LL-37 peptides by screening the Nebraska Transposon Mutant Library. In total, 24 resistant genes were identified. Among them, six mutants, including the one with the known membrane-modifying gene (mprF) disabled, became more membrane permeable to the LL-37 engineered peptide 17BIPHE2 than the wild type...

In the quest for new antibiotics, two novel engineered Cationic Antimicrobial Peptides (eCAPs) have been rationally designed. WLBU2 and D8 (all 8 valines are the D-enantiomer) efficiently kill both gram-negative and -positive bacteria, but WLBU2 is toxic and D8 non-toxic to eukaryotic cells. We explore protein secondary structure, location of peptides in six lipid model membranes, changes in membrane structure and pore evidence.  We suggest that protein secondary structure is not a critical determinant of bactericidal activity, but that membrane thinning and dual location of WLBU2 and D8 in the membrane headgroup and hydrocarbon region may be important...

Colicin U is a protein produced by the bacterium Shigella boydii (serovars 1 and 8). It exerts antibacterial activity against strains of the enterobacterial genera Shigella and Escherichia. Here we report that colicin U forms voltage-dependent pores in planar lipid membranes; its single-pore conductance was found to be about 22 pS in 1M KCl, at pH 6 under 80 mV in asolectin bilayers. In agreement with the high degree of homology between their C-terminal domains, colicin U shares some pore characteristics with the related colicins A and B...

BACKGROUND: Antibiotic-resistant pathogens are an emerging threat in this century. Epinecidin-1 is a multi-functional Antimicrobial Peptide (AMP) produced by Orange-spotted grouper (Epinephelus coioides) has been shown to have extensive potentials as an alternative for current antibiotics. Due to the huge costs for the study and the production of a new drug, if an antimicrobial peptide has other beneficial functions in addition to antimicrobial activities, it would be preferred. METHODS: In this study, properties and applications of Epinecidin-1 were investigated and addressed comprehensively...

The development and rapid spread of multidrug resistant (MDR) bacteria cause severe public crises. New antibacterial compounds are urgently needed to treat bacterial infections. By circumventing the disadvantages of cationic peptides here, we engineered a short, linear, low-cationic peptide bacaucin-1a, which exhibited remarkable antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). Bacaucin-1a was efficient in the prevention of MRSA associated infections in both in vitro and in vivo models with a unique mode of action...

In recent years, the overuse of antibiotics has become very serious. Many pathogenic bacteria have become resistant to them, with serious potential health consequences. Thus, it is urgent that we develop new antibiotic drugs. Antimicrobial peptides (AMPs) are important endogenous antibacterial molecules that contribute to immunity. Most have spectral antibacterial properties and do not confer drug resistance. In this paper, an 11-residue peptide (LFcinB18⁻28) with a sequence of KCRRWQWRMKK was modified by amino acid substitution to form a symmetrical amino acid sequence...

The rapid emergence of antibiotic-resistant bacterial "superbugs" with concomitant treatment failure and high mortality rates presents a severe threat to global health. The superbug risk is further exacerbated by chronic infections generated from antibiotic-resistant biofilms that render them refractory to available treatments. We hypothesized that efficient antimicrobial agents could be generated through careful engineering of hydrophobic and cationic domains in a synthetic semirigid polymer scaffold, mirroring and amplifying attributes of antimicrobial peptides...

CXCL14 is a CXC chemokine family that exhibits antimicrobial activity and contains an amphipathic cationic α-helical region in the C-terminus, a characteristic structure of antimicrobial peptides (AMPs). In this study, we designed three analogs of CXCL1459-75 (named CXCL14-C17) corresponding to the C-terminal α-helix of CXCL14, which displayed potential antimicrobial activity against a wide variety of gram-negative and gram-positive bacteria with minimum inhibitory concentrations of 4-16 μM without mammalian cell toxicity...

Eradication of established biofilm communities of pathogenic bacteria is one of the pending challenges in the development of new antimicrobial agents. In particular, the dreaded nosocomial Pseudomonas aeruginosa forms microbial communities that offer an enhanced resistance to conventional antibiotics. Recently, we have described an engineered antimicrobial peptide derived from the human RNase3, also named the eosinophil cationic protein (ECP), RN3 (5-36), which combines bactericidal activity with high cell agglutination and lipopolysaccharide (LPS) affinity...

OBJECTIVES: Bacterial biofilm-dependent infections (e.g. cystic fibrosis, surgical sites, and medical implants) are associated with enhanced drug-resistance and are thus difficult to eradicate. The goal of this study was to systematically compare three distinct classes of antimicrobial peptides (AMPs) that include the clinically used antibiotic colistin, the natural AMP LL37, the engineered cationic-AMP WLBU2, and four commonly used antibiotics with different bactericidal mechanisms (tobramycin, ciprofloxacin, ceftazidime, and vancomycin) for biofilm prevention properties...

Mastoparan (MP) peptides, distributed in insect venoms, induce a local inflammatory response post envenomation. Most endogenous MPs share common structural elements within a tetradecapeptide sequence that adopts an amphipathic helix whilst traversing biological membranes and when bound to an intracellular protein target. Rational modifications to increase cationic charge density and amphipathic helicity engineered mitoparan (MitP), a mitochondriotoxic bioportide and potent secretagogue. Following intracellular translocation, MitP is accreted by mitochondria thus indicating additional utility as an antimicrobial agent...