Synthetic molecular evolution of host cell-compatible, antimicrobial peptides effective against drug-resistant, biofilm-forming bacteria

Starr, Charles G.; Ghimire, Jenisha; Guha, Shantanu; Hoffmann, Joseph P.; Wang, Yihui; Sun, Leisheng; Landreneau, Brooke N.; Kolansky, Zachary D.; Kilanowski‐Doroh, Isabella; Sammarco, Mimi C.; Morici, Lisa A.; Wimley, William C.

doi:10.1073/pnas.1918427117

Cited by 48 publications

(106 citation statements)

References 57 publications

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“…We envision that the next step toward development of peptide antiviral drugs will be synthetic molecular evolution in which a peptide library based on the principles revealed in this work will be screened simultaneously for potent antiviral activity and lack of toxicity in the presence of concentrated host cells and serum. We have recently applied this approach to the discovery of host cell-compatible antibacterial peptides (47) and successfully identified antibacterial peptides with very strong selectivity for bacteria over host cells. We expect the same result to be achievable in one generation of synthetic molecular evolution of antiviral peptides.…”

Section: Discussionmentioning

confidence: 99%

Broad-Spectrum Antiviral Entry Inhibition by Interfacially Active Peptides

Hoffmann

Guha

et al. 2020

J Virol

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Numerous peptides inhibit the entry of enveloped viruses into cells. Some of these peptides have been shown to inhibit multiple unrelated viruses. We have suggested that such broad-spectrum antiviral peptides share a property called interfacial activity; they are somewhat hydrophobic and amphipathic, with a propensity to interact with the interfacial zones of lipid bilayer membranes. In this study, we further tested the hypothesis that such interfacial activity is a correlate of broad-spectrum antiviral activity. In this study, several families of peptides, selected for the ability to partition into and disrupt membrane integrity but with no known antiviral activity, were tested for the ability to inhibit multiple diverse enveloped viruses. These include Lassa pseudovirus, influenza virus, dengue virus type 2, herpes simplex virus 1, and nonenveloped human adenovirus 5. Various families of interfacially active peptides caused potent inhibition of all enveloped viruses tested at low and submicromolar concentrations, well below the range in which they are toxic to mammalian cells. These membrane-active peptides block uptake and fusion with the host cell by rapidly and directly interacting with virions, destabilizing the viral envelope, and driving virus aggregation and/or intervirion envelope fusion. We speculate that the molecular characteristics shared by these peptides can be exploited to enable the design, optimization, or molecular evolution of novel broad-spectrum antiviral therapeutics. IMPORTANCE New classes of antiviral drugs are needed to treat the ever-changing viral disease landscape. Current antiviral drugs treat only a small number of viral diseases, leaving many patients with established or emerging infections to be treated solely with supportive care. Recent antiviral peptide research has produced numerous membrane-interacting peptides that inhibit diverse enveloped viruses in vitro and in vivo. Peptide therapeutics are becoming more common, with over 60 FDA-approved peptides for clinical use. Included in this class of therapeutics is enfuvirtide, a 36-residue peptide drug that inhibits HIV entry/fusion. Due to their broad-spectrum mechanism of action and enormous potential sequence diversity, peptides that inhibit virus entry could potentially fulfill the need for new antiviral therapeutics; however, a better understanding of their mechanism is needed for the optimization or evolution of sequence design to combat the wide landscape of viral disease.

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Section: Discussionmentioning

confidence: 99%

Broad-Spectrum Antiviral Entry Inhibition by Interfacially Active Peptides

Hoffmann

Guha

et al. 2020

J Virol

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“…7d). This is an important observation as most of the studies have focused on effect of sequestration of AMPs by host cells or proteins on the apparent MIC in situ (39, 40). In recent study using a synthetic and naturally occurring peptide, ‘ARVA’ and PMAP-23, respectively, it was determined that ~107 peptide molecules/cell is required for complete killing (40, 41).…”

Section: Resultsmentioning

confidence: 98%

“…In recent study using a synthetic and naturally occurring peptide, ‘ARVA’ and PMAP-23, respectively, it was determined that ~107 peptide molecules/cell is required for complete killing (40, 41). However, not all peptides are affected equally by the presence of host cells like RBCs (39, 42). In the crowded environment like gut, microbial population density is much higher than the host cells (43).…”

Section: Resultsmentioning

confidence: 99%

Charged Gram-positive species sequester and decrease the potency of pediocin PA-1 in mixed microbial settings

Trivedi

Nair

2020

Preprint

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15Antimicrobial peptides (AMPs) have gained attention recently due to increasing antibiotic 16 resistance amongst pathogens. Most AMPs are cationic in nature and their preliminary 17 interactions with the negatively charged cell surface is mediated by electrostatic attraction. This 18 is followed by pore formation, which is either receptor-dependent or -independent and leads to 19 cell death. Typically, AMPs are characterized by their killing activity using bioactivity assays 20 to determine host range and degree of killing. However, cell surface binding is independent 21 from killing. Most of the studies performed to-date have attempted to quantify the peptide 22 binding using artificial membranes. Here, we use the narrow-spectrum class IIa bacteriocin 23 AMP pediocin PA-1 conjugated to a fluorescent dye as a probe to monitor cell surface binding. 24We developed a flow cytometry-based assay to quantify the strength of binding in target and 25 non-target species. Through our binding assays, we found a strong positive correlation between 26 cell surface charge and pediocin PA-1 binding. Interestingly, we also found inverse correlation 27 between zeta potential and pediocin PA-1 binding, the correlation coefficient for which 28 improved when only Gram-positives were considered. We also show the effect of the presence 29 of protein, salt, polycationic species, and other non-target species on the binding of pediocin 30PA-1 to the target organism. We conclude that the of presence of highly charged non-target 31 species, as well as solutes, can decrease the binding, and the apparent potency, of pediocin PA-32 1. Thus, these outcomes are highly significant to the use of pediocin PA-1 and related AMPs 33 in mixed microbial settings such as those found in the gut microbiota. 34 35

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“…Different strategies are trying to overcome the antibiotic resistance. In this sense, new therapies are currently being searched, either with antibiotics that have high rates of susceptibility, such as levofloxacin (LEV), an agent with clinical value and a high anti-staphylococcal activity [ 6 ], or using newly synthesized molecules, such as antimicrobial peptides, which have been recently considered one of the most relevant therapeutic approaches in the treatment of biofilms [ 7 , 8 , 9 , 10 ]. Among these new therapeutic strategies, dendritic systems of carbosilane nature have shown to be a promising solution.…”

Section: Introductionmentioning

confidence: 99%

Effect of the Combination of Levofloxacin with Cationic Carbosilane Dendron and Peptide in the Prevention and Treatment of Staphylococcus aureus Biofilms

et al. 2021

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Antibiotic resistance and biofilm-related infections, persistent in conventional antimicrobial treatment, are continuously increasing and represent a major health problem worldwide. Therefore, the development of new effective treatments to prevent and treat biofilm-related infections represents a crucial challenge. Unfortunately, the extensive use of antibiotics has led to an increase of resistant bacteria with the subsequent loss of effectivity of commercial antibiotics, mainly due to antibiotic resistance and the ability of some bacteria to form microbial communities in biotic or abiotic surfaces (biofilms). In some cases, these biofilms are resistant to high concentrations of antibiotics that lead to treatment failure and recurrence of the associated infections. In the fight against microbial resistance, the combination of traditional antibiotics with new compounds (combination therapy) is an alternative that is becoming more extensive in the medical field. In this work, we studied the cooperative effects between levofloxacin, an approved antibiotic, and peptides or cationic dendritic molecules, compounds that are emerging as a feasible solution to overcome the problem of microbial resistance caused by pathogenic biofilms. We studied a new therapeutic approach that involves the use of levofloxacin in combination with a cationic carbosilane dendron, called MalG2(SNHMe2Cl)4, or a synthetic cell-penetrating peptide, called gH625, conjugated to the aforementioned dendron. To carry out the study, we used two combinations (1) levofloxacin/dendron and (2) levofloxacin/dendron-peptide nanoconjugate. The results showed the synergistic effect of the combination therapy to treat Staphylococcus aureus biofilms. In addition, we generated a fluorescein labeled peptide that allowed us to observe the conjugate (dendron-peptide) localization throughout the bacterial biofilm by confocal laser scanning microscopy.

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Synthetic molecular evolution of host cell-compatible, antimicrobial peptides effective against drug-resistant, biofilm-forming bacteria

Cited by 48 publications

References 57 publications

Broad-Spectrum Antiviral Entry Inhibition by Interfacially Active Peptides

Broad-Spectrum Antiviral Entry Inhibition by Interfacially Active Peptides

Charged Gram-positive species sequester and decrease the potency of pediocin PA-1 in mixed microbial settings

Effect of the Combination of Levofloxacin with Cationic Carbosilane Dendron and Peptide in the Prevention and Treatment of Staphylococcus aureus Biofilms

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