Antimicrobial peptides provide wider coverage for targeting drug‐resistant bacterial pathogens

Amiss, Anna S.; Henriques, Sónia Troeira; Lawrence, Nicole

doi:10.1002/pep2.24246

Cited by 8 publications

(6 citation statements)

References 196 publications

(379 reference statements)

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“…[ 42 ] It has been suggested that accumulation of AMPs in the bacterial membrane causes increased permeability due to the loss of membrane integrity (e.g., destabilization of the LPS layer). [ 43 ] With peptoid 29 , the mechanism leading to the internalization of the compound at low concentrations is not fully understood. However, the observed inhibition of bacterial metabolism and the increased intracellular RI values with fluorescent images proves peptoid internalization in the absence of visible pore formation at low peptoid concentrations.…”

Section: Discussionmentioning

confidence: 99%

Real‐Time Monitoring of Multitarget Antimicrobial Mechanisms of Peptoids Using Label‐Free Imaging with Optical Diffraction Tomography

et al. 2023

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Antimicrobial peptides (AMPs) are promising therapeutics in the fight against multidrug‐resistant bacteria. As a mimic of AMPs, peptoids with N‐substituted glycine backbone have been utilized for antimicrobials with resistance against proteolytic degradation. Antimicrobial peptoids are known to kill bacteria by membrane disruption; however, the nonspecific aggregation of intracellular contents is also suggested as an important bactericidal mechanism. Here,structure‐activity relationship (SAR) of a library of indole side chain‐containing peptoids resulting in peptoid 29 as a hit compound is investigated. Then, quantitative morphological analyses of live bacteria treated with AMPs and peptoid 29 in a label‐free manner using optical diffraction tomography (ODT) are performed. It is unambiguously demonstrated that both membrane disruption and intracellular biomass flocculation are primary mechanisms of bacterial killing by monitoring real‐time morphological changes of bacteria. These multitarget mechanisms and rapid action can be a merit for the discovery of a resistance‐breaking novel antibiotic drug.

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Section: Discussionmentioning

confidence: 99%

Real‐Time Monitoring of Multitarget Antimicrobial Mechanisms of Peptoids Using Label‐Free Imaging with Optical Diffraction Tomography

et al. 2023

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“…Here we describe the rational optimization of the selective, membrane-active PDIP scaffold. We identified an antiplasmodial potency-enhancing substitution (E16K) and incorporated this into a stable and selective scaffold (24) to produce a backbone cyclic PDIP analogue (26) with low micromolar activity against in vitro P. falciparum parasites (see Figure 7). The outcomes of this study represent a practical advance in developing the PDIP scaffold as an antimalarial molecule and provide a framework for monitoring and selecting desirable properties during peptide-based drug development.…”

Section: ■ Conclusionmentioning

confidence: 99%

Enhancing the Intrinsic Antiplasmodial Activity and Improving the Stability and Selectivity of a Tunable Peptide Scaffold Derived from Human Platelet Factor 4

Lawrence,

Handley,

de Veer

et al. 2024

ACS Infect. Dis.

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The control of malaria, a disease caused by Plasmodium parasites that kills over half a million people every year, is threatened by the continual emergence and spread of drug resistance. Therefore, new molecules with different mechanisms of action are needed in the antimalarial drug development pipeline. Peptides developed from host defense molecules are gaining traction as anti-infectives due to theood of inducing drug resistance. Human platelet factor 4 (PF4) has intrinsic activity against P. falciparum, and a macrocyclic helix−loop−helix peptide derived from its active domain recapitulates this activity. In this study, we used a stepwise approach to optimize first-generation PF4-derived internalization peptides (PDIPs) by producing analogues with substitutions to charged and hydrophobic amino acid residues or with modifications to terminal residues including backbone cyclization. We evaluated the in vitro activity of PDIP analogues against P. falciparum compared to their overall helical structure, resistance to breakdown by serum proteases, selective binding to negatively charged membranes, and hemolytic activity. Next, we combined antiplasmodial potency-enhancing substitutions that retained favorable membrane and cell-selective properties onto the most stable scaffold to produce a backbone cyclic PDIP analogue with four-fold improved activity against P. falciparum compared to first-generation peptides. These studies demonstrate the ability to modify PDIP to select for and combine desirable properties and further validate the suitability of this unique peptide scaffold for developing a new molecule class that is distinct from existing antimalarial drugs.

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“…Their toxicity and stability in vivo are two drawbacks that restrict their use [124]. Another drawback is their inherent limitations as peptides, such as stability, cytotoxicity, and bioavailability [125]. Natural AMPs are only useful for topical applications due to their pharmacological characteristics [126].…”

Section: Antimicrobial Peptidesmentioning

confidence: 99%

The Battle Against Antibiotic Resistance: Novel Therapeutic Options for Acinetobacter baumannii

Emami,

Pirbonyeh,

Javanmardi

2023

Acinetobacter Baumannii - The Rise of a Resistant Pathogen

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Undoubtedly, Acinetobacter baumannii stands out as one of the most effective bacteria responsible for nosocomial infections within the healthcare system. Due to its multidrug-resistant nature and the frequency of outbreaks that it causes the treatment of infections caused by this bacterium is challenging, antimicrobial combination therapy has been utilized to treat multidrug resistance Gram-negatives when monotherapy is ineffective. In contrast to antibiotics or short peptides, which possess only the capacity to bind and regulate a specific target, antibodies exhibit supplementary properties attributed to their Fc region, including opsonophagocytic activity, the agglutination process, and activation of the complement system. The criticality of antibodies is exemplified in triggering immunity against A. baumannii, stimulating protective mechanisms, preventing bacterial attachment to epithelial cells, opsonization, and complement-dependent bacterial destruction. Given antibodies’ significant role in humoral immunity, monoclonal antibodies (mAbs) may be generated to specifically bind to certain targets, thereby providing supplemental defense as a form of immunotherapy or passive immunization. Many encouraging tactics, ranging from phage therapy to immunotherapy, are being scrutinized for their efficacy in treating infectious diseases, thus shaping the future treatment landscape.

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Antimicrobial peptides provide wider coverage for targeting drug‐resistant bacterial pathogens

Cited by 8 publications

References 196 publications

Real‐Time Monitoring of Multitarget Antimicrobial Mechanisms of Peptoids Using Label‐Free Imaging with Optical Diffraction Tomography

Real‐Time Monitoring of Multitarget Antimicrobial Mechanisms of Peptoids Using Label‐Free Imaging with Optical Diffraction Tomography

Enhancing the Intrinsic Antiplasmodial Activity and Improving the Stability and Selectivity of a Tunable Peptide Scaffold Derived from Human Platelet Factor 4

The Battle Against Antibiotic Resistance: Novel Therapeutic Options for Acinetobacter baumannii

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