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Structure–Activity Studies of Antibacterials and Potentiators of Antibiotics

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 31759

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Prof. Dr. Henrik Franzyk

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Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
Interests: antimicrobial peptides; immunomodulation; drug delivery
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Prof. Dr. Paul Robert Hansen

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Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark
Interests: antimicrobial peptides; drug delivery
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Dear Colleagues,

Although antibiotics have saved millions of lives, the current rapid emergence of multidrug-resistant bacteria has generated an urgent need to identify new antibacterials and explore alternative strategies to combat these pathogens. In particular, two strategies are of interest: (i) structure–activity studies of antibacterials including antimicrobial peptides (AMPs) and peptidomimetics, and (ii) potentiators of antibiotics (e.g., studies of a broad spectrum of antibiotics in combination with potentiators against important veterinary/human pathogens).

AMPs are considered interesting potential new antibiotics, as they constitute an essential part of the innate immune system in all multicellular organisms. Additionally, their broad-spectrum activity, fast killing mechanisms, and membrane-associated mode of action confers a low tendency for resistance development. Structure–activity studies of antibacterials (including antimicrobial peptides and peptidomimetics) provide important knowledge on how to design new potential antibacterials. Such structure–activity studies include modifications conferring enhanced antibacterial activity while keeping the toxic side effects at an acceptable level.

The discovery of new compounds possessing the capacity to potentiate existing antibacterials has received considerable attention in recent years. Such compounds may enable the circumvention of already developed resistance by resensitizing multidrug-resistant pathogenic bacteria to commonly used antibiotics.

For this Special Issue entitled” Structure–Activity Studies of Antibacterials and Potentiators of Antibiotics” we invite authors to submit articles covering all aspects of this theme.

Assoc. Prof. Henrik Franzyk
Assoc. Prof. Paul Robert Hansen
Guest Editors

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Keywords

Structure-activity study
Antibacterials
Potentiators
Peptides
Peptidomimetics
Human pathogens
Multi-drug resistance

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Published Papers (9 papers)

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Research

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17 pages, 2014 KiB

Open AccessArticle

Peptide/β-Peptoid Hybrids with Ultrashort PEG-Like Moieties: Effects on Hydrophobicity, Antibacterial Activity and Hemolytic Properties

by Nicki Frederiksen, Stavroula Louka, Chirag Mudaliar, Ilona Domraceva, Agrita Kreicberga, Osvalds Pugovics, Dorota Żabicka, Magdalena Tomczak, Weronika Wygoda, Fredrik Björkling and Henrik Franzyk

Int. J. Mol. Sci. 2021, 22(13), 7041; https://doi.org/10.3390/ijms22137041 - 30 Jun 2021

Cited by 6 | Viewed by 2645

Abstract

PEGylation of antimicrobial peptides as a shielding tool that increases stability toward proteolytic degradation typically leads to concomitant loss of activity, whereas incorporation of ultrashort PEG-like amino acids (sPEGs) remains essentially unexplored. Here, modification of a peptide/β-peptoid hybrid with sPEGs was examined with respect to influence on hydrophobicity, antibacterial activity and effect on viability of mammalian cells for a set of 18 oligomers. Intriguingly, the degree of sPEG modification did not significantly affect hydrophobicity as measured by retention in reverse-phase HPLC. Antibacterial activity against both wild-type and drug-resistant strains of Escherichia coli and Acinetobacter baumannii (both Gram-negative pathogens) was retained or slightly improved (MICs in the range 2–16 µg/mL equal to 0.7–5.2 µM). All compounds in the series exhibited less than 10% hemolysis at 400 µg/mL. While the number of sPEG moieties appeared not to be clearly correlated with hemolytic activity, a trend toward slightly increased hemolytic activity was observed for analogues displaying the longest sPEGs. In contrast, within a subseries the viability of HepG2 liver cells was least affected by analogues displaying the longer sPEGs (with IC₅₀ values of ~1280 µg/mL) as compared to most other analogues and the parent peptidomimetic (IC₅₀ values in the range 330–800 µg/mL). Full article

(This article belongs to the Special Issue Structure–Activity Studies of Antibacterials and Potentiators of Antibiotics)

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14 pages, 782 KiB

Open AccessArticle

Peptide/β-Peptoid Hybrids with Activity against Vancomycin-Resistant Enterococci: Influence of Hydrophobicity and Structural Features on Antibacterial and Hemolytic Properties

by Martin Vestergaard, Bolette Skive, Ilona Domraceva, Hanne Ingmer and Henrik Franzyk

Int. J. Mol. Sci. 2021, 22(11), 5617; https://doi.org/10.3390/ijms22115617 - 25 May 2021

Cited by 7 | Viewed by 2981

Abstract

Infections with enterococci are challenging to treat due to intrinsic resistance to several antibiotics. Especially vancomycin-resistant Enterococcus faecium and Enterococcus faecalis are of considerable concern with a limited number of efficacious therapeutics available. From an initial screening of 20 peptidomimetics, 11 stable peptide/β-peptoid hybrids were found to have antibacterial activity against eight E. faecium and E. faecalis isolates. Microbiological characterization comprised determination of minimal inhibitory concentrations (MICs), probing of synergy with antibiotics in a checkerboard assay, time–kill studies, as well as assessment of membrane integrity. E. faecium isolates proved more susceptible than E. faecalis isolates, and no differences in susceptibility between the vancomycin-resistant (VRE) and -susceptible E. faecium isolates were observed. A test of three peptidomimetics (Ac-[hArg-βNsce]₆-NH₂, Ac-[hArg-βNsce-Lys-βNspe]₃-NH₂ and Oct-[Lys-βNspe]₆-NH₂) in combination with conventional antibiotics (vancomycin, gentamicin, ciprofloxacin, linezolid, rifampicin or azithromycin) revealed no synergy. The same three potent analogues were found to have a bactericidal effect with a membrane-disruptive mode of action. Peptidomimetics Ac-[hArg-βNsce-Lys-βNspe]₃-NH₂ and Oct-[Lys-βNspe]₆-NH₂ with low MIC values (in the ranges 2–8 µg/mL and 4–16 µg/mL against E. faecium and E. faecalis, respectively) and displaying weak cytotoxic properties (i.e., <10% hemolysis at a ~100-fold higher concentration than their MICs; IC₅₀ values of 73 and 41 µg/mL, respectively, against HepG2 cells) were identified as promising starting points for further optimization studies. Full article

(This article belongs to the Special Issue Structure–Activity Studies of Antibacterials and Potentiators of Antibiotics)

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18 pages, 4852 KiB

Open AccessArticle

Aggregation and Its Influence on the Bioactivities of a Novel Antimicrobial Peptide, Temporin-PF, and Its Analogues

by Yu Zai, Xinping Xi, Zhuming Ye, Chengbang Ma, Mei Zhou, Xiaoling Chen, Shirley W. I. Siu, Tianbao Chen, Lei Wang and Hang Fai Kwok

Int. J. Mol. Sci. 2021, 22(9), 4509; https://doi.org/10.3390/ijms22094509 - 26 Apr 2021

Cited by 26 | Viewed by 3711

Abstract

Temporin is an antimicrobial peptide (AMP) family discovered in the skin secretion of ranid frog that has become a promising alternative for conventional antibiotic therapy. Herein, a novel temporin peptide, Temporin-PF (TPF), was successfully identified from Pelophylax fukienensis. It exhibited potent activity against Gram-positive bacteria, but no effect on Gram-negative bacteria. Additionally, TPF exhibited aggregation effects in different solutions. Three analogs were further designed to study the relationship between the aggregation patterns and bioactivities, and the MD simulation was performed for revealing the pattern of the peptide assembly. As the results showed, all peptides were able to aggregate in the standard culture media and salt solutions, especially CaCl₂ and MgCl₂ buffers, where the aggregation was affected by the concentration of the salts. MD simulation reported that all peptides were able to form oligomers. The parent peptide assembly depended on the hydrophobic interaction via the residues in the middle domain of the sequence. However, the substitution of Trp/D-Trp resulted in an enhanced inter-peptide interaction in the zipper-like domain and eliminated overall biological activities. Our study suggested that introducing aromaticity at the zipper-like domain for temporin may not improve the bioactivities, which might be related to the formation of aggregates via the inter-peptide contacts at the zipper-like motif domain, and it could reduce the binding affinity to the lipid membrane of microorganisms. Full article

(This article belongs to the Special Issue Structure–Activity Studies of Antibacterials and Potentiators of Antibiotics)

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16 pages, 4578 KiB

Open AccessArticle

Structural and Mechanismic Studies of Lactophoricin Analog, Novel Antibacterial Peptide

by Minseon Kim, Jinyoung Son and Yongae Kim

Int. J. Mol. Sci. 2021, 22(7), 3734; https://doi.org/10.3390/ijms22073734 - 2 Apr 2021

Viewed by 2333

Abstract

Naturally derived antibacterial peptides exhibit excellent pharmacological action without the risk of resistance, suggesting a potential role as biologicals. Lactophoricin-I (LPcin-I), found in the proteose peptone component-3 (PP3; lactophorin) of bovine milk, is known to exhibit antibiotic activity against Gram-positive and Gram-negative bacteria. Accordingly, we derived a new antibacterial peptide and investigated its structure–function relationship. This study was initiated by designing antibacterial peptide analogs with better antibacterial activity, less cytotoxicity, and shorter amino acid sequences based on LPcin-I. The structural properties of antibacterial peptide analogs were investigated via spectroscopic analysis, and the antibacterial activity was confirmed by measurement of the minimal inhibitory concentration (MIC). The structure and mechanism of the antibacterial peptide analog in the cell membrane were also studied via solution-state nuclear magnetic resonance (NMR) and solid-state NMR spectroscopy. Through ¹⁵N one-dimensional and two-dimensional NMR experiments and ³¹P NMR experiments, we suggest the 3D morphology and antibacterial mechanism in the phospholipid bilayer of the LPcin analog. This study is expected to establish a system for the development of novel antibacterial peptides and to establish a theoretical basis for research into antibiotic substitutes. Full article

(This article belongs to the Special Issue Structure–Activity Studies of Antibacterials and Potentiators of Antibiotics)

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20 pages, 11791 KiB

Open AccessArticle

Conformational Changes of Anoplin, W-MreB_1–9, and (KFF)₃K Peptides near the Membranes

by Monika Wojciechowska, Joanna Miszkiewicz and Joanna Trylska

Int. J. Mol. Sci. 2020, 21(24), 9672; https://doi.org/10.3390/ijms21249672 - 18 Dec 2020

Cited by 11 | Viewed by 3374

Abstract

Many peptides interact with biological membranes, but elucidating these interactions is challenging because cellular membranes are complex and peptides are structurally flexible. To contribute to understanding how the membrane-active peptides behave near the membranes, we investigated peptide structural changes in different lipid surroundings. We focused on two antimicrobial peptides, anoplin and W-MreB_1–9, and one cell-penetrating peptide, (KFF)₃K. Firstly, by using circular dichroism spectroscopy, we determined the secondary structures of these peptides when interacting with micelles, liposomes, E. coli lipopolysaccharides, and live E. coli bacteria. The peptides were disordered in the buffer, but anoplin and W-MreB_1–9 displayed lipid-induced helicity. Yet, structural changes of the peptide depended on the composition and concentration of the membranes. Secondly, we quantified the destructive activity of peptides against liposomes by monitoring the release of a fluorescent dye (calcein) from the liposomes treated with peptides. We observed that only for anoplin and W-MreB_1–9 calcein leakage from liposomes depended on the peptide concentration. Thirdly, bacterial growth inhibition assays showed that peptide conformational changes, evoked by the lipid environments, do not directly correlate with the antimicrobial activity of the peptides. However, understanding the relation between peptide structural properties, mechanisms of membrane disruption, and their biological activities can guide the design of membrane-active peptides. Full article

(This article belongs to the Special Issue Structure–Activity Studies of Antibacterials and Potentiators of Antibiotics)

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13 pages, 2619 KiB

Open AccessArticle

The Antimicrobial Peptide Temporin G: Anti-Biofilm, Anti-Persister Activities, and Potentiator Effect of Tobramycin Efficacy Against Staphylococcus aureus

by Bruno Casciaro, Maria Rosa Loffredo, Floriana Cappiello, Guendalina Fabiano, Luisa Torrini and Maria Luisa Mangoni

Int. J. Mol. Sci. 2020, 21(24), 9410; https://doi.org/10.3390/ijms21249410 - 10 Dec 2020

Cited by 20 | Viewed by 2751

Abstract

Bacterial biofilms are a serious threat for human health, and the Gram-positive bacterium Staphylococcus aureus is one of the microorganisms that can easily switch from a planktonic to a sessile lifestyle, providing protection from a large variety of adverse environmental conditions. Dormant non-dividing cells with low metabolic activity, named persisters, are tolerant to antibiotic treatment and are the principal cause of recalcitrant and resistant infections, including skin infections. Antimicrobial peptides (AMPs) hold promise as new anti-infective agents to treat such infections. Here for the first time, we investigated the activity of the frog-skin AMP temporin G (TG) against preformed S. aureus biofilm including persisters, as well as its efficacy in combination with tobramycin, in inhibiting S. aureus growth. TG was found to provoke ~50 to 100% reduction of biofilm viability in the concentration range from 12.5 to 100 µM vs ATCC and clinical isolates and to be active against persister cells (about 70–80% killing at 50–100 µM). Notably, sub-inhibitory concentrations of TG in combination with tobramycin were able to significantly reduce S. aureus growth, potentiating the antibiotic power. No critical cytotoxicity was detected when TG was tested in vitro up to 100 µM against human keratinocytes, confirming its safety profile for the development of a new potential anti-infective drug, especially for treatment of bacterial skin infections. Full article

(This article belongs to the Special Issue Structure–Activity Studies of Antibacterials and Potentiators of Antibiotics)

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18 pages, 1455 KiB

Open AccessArticle

Novel Cyclic Lipopeptide Antibiotics: Effects of Acyl Chain Length and Position

by Signe Kaustrup Jensen, Thomas T. Thomsen, Alberto Oddo, Henrik Franzyk, Anders Løbner-Olesen and Paul R. Hansen

Int. J. Mol. Sci. 2020, 21(16), 5829; https://doi.org/10.3390/ijms21165829 - 13 Aug 2020

Cited by 16 | Viewed by 4198

Abstract

Multidrug-resistant bacteria are a global health problem. One of the last-resort antibiotics against Gram-negative bacteria is the cyclic lipopeptide colistin, displaying a flexible linker with a fatty acid moiety. The aim of the present project was to investigate the effect on antimicrobial activity of introducing fatty acid moieties of different lengths and in different positions in a cyclic peptide, S3(B), containing a flexible linker. The lipidated analogues of S3(B) were synthesized by 9-fluorenylmethoxycarbonyl (Fmoc) solid-phase peptide synthesis. Following assembly of the linear peptide by Fmoc solid-phase peptide synthesis, on-resin head-to-tail cyclization and fatty acid acylation were performed. The antimicrobial activity was determined against the ESKAPE pathogens, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli. Furthermore, hemolytic activity was determined against human erythrocytes. A total of 18 cyclic lipopeptides were synthesized and characterized. It was found that introduction of fatty acids in positions next to the flexible linker was more strongly linked to antimicrobial activity. The fatty acid length altered the overall hydrophobicity, which was the driving force for both high antimicrobial and hemolytic activity. Peptides became highly hemolytic when carbon-chain length exceeded 10 (i.e., C₁₀), overlapping with the optimum for antimicrobial activity (i.e., C₈–C₁₂). The most promising candidate (C₈)⁵ showed antimicrobial activity corresponding to that of S3(B), but with an improved hemolytic profile. Finally, (C₈)⁵ was further investigated in a time-kill experiment. Full article

(This article belongs to the Special Issue Structure–Activity Studies of Antibacterials and Potentiators of Antibiotics)

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21 pages, 2131 KiB

Open AccessArticle

Synthesis of Fmoc-Triazine Amino Acids and Its Application in the Synthesis of Short Antibacterial Peptidomimetics

by Pethaiah Gunasekaran, Eun Young Kim, Jian Lee, Eun Kyoung Ryu, Song Yub Shin and Jeong Kyu Bang

Int. J. Mol. Sci. 2020, 21(10), 3602; https://doi.org/10.3390/ijms21103602 - 20 May 2020

Cited by 12 | Viewed by 4393

Abstract

To combat the escalating rise of antibacterial resistance, the development of antimicrobial peptides (AMPs) with a unique mode of action is considered an attractive strategy. However, proteolytic degradation of AMPs remains the greatest challenge in their transformation into therapeutics. Herein, we synthesized Fmoc-triazine amino acids that differ from each other by anchoring either cationic or hydrophobic residues. These unnatural amino acids were adopted for solid-phase peptide synthesis (SPPS) to synthesize a series of amphipathic antimicrobial peptidomimetics. From the antimicrobial screening, we found that the trimer, BJK-4 is the most potent short antimicrobial peptidomimetic without showing hemolytic activity and it displayed enhanced proteolytic stability. Moreover, the mechanism of action to kill bacteria was found to be an intracellular targeting. Full article

(This article belongs to the Special Issue Structure–Activity Studies of Antibacterials and Potentiators of Antibiotics)

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Review

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37 pages, 4518 KiB

Open AccessReview

Amphiphilic Aminoglycosides as Medicinal Agents

by Clément Dezanet, Julie Kempf, Marie-Paule Mingeot-Leclercq and Jean-Luc Décout

Int. J. Mol. Sci. 2020, 21(19), 7411; https://doi.org/10.3390/ijms21197411 - 8 Oct 2020

Cited by 16 | Viewed by 4381

Abstract

The conjugation of hydrophobic group(s) to the polycationic hydrophilic core of the antibiotic drugs aminoglycosides (AGs), targeting ribosomal RNA, has led to the development of amphiphilic aminoglycosides (AAGs). These drugs exhibit numerous biological effects, including good antibacterial effects against susceptible and multidrug-resistant bacteria due to the targeting of bacterial membranes. In the first part of this review, we summarize our work in identifying and developing broad-spectrum antibacterial AAGs that constitute a new class of antibiotic agents acting on bacterial membranes. The target-shift strongly improves antibiotic activity against bacterial strains that are resistant to the parent AG drugs and to antibiotic drugs of other classes, and renders the emergence of resistant Pseudomonas aeruginosa strains highly difficult. Structure–activity and structure–eukaryotic cytotoxicity relationships, specificity and barriers that need to be crossed in their development as antibacterial agents are delineated, with a focus on their targets in membranes, lipopolysaccharides (LPS) and cardiolipin (CL), and the corresponding mode of action against Gram-negative bacteria. At the end of the first part, we summarize the other recent advances in the field of antibacterial AAGs, mainly published since 2016, with an emphasis on the emerging AAGs which are made of an AG core conjugated to an adjuvant or an antibiotic drug of another class (antibiotic hybrids). In the second part, we briefly illustrate other biological and biochemical effects of AAGs, i.e., their antifungal activity, their use as delivery vehicles of nucleic acids, of short peptide (polyamide) nucleic acids (PNAs) and of drugs, as well as their ability to cleave DNA at abasic sites and to inhibit the functioning of connexin hemichannels. Finally, we discuss some aspects of structure–activity relationships in order to explain and improve the target selectivity of AAGs. Full article

(This article belongs to the Special Issue Structure–Activity Studies of Antibacterials and Potentiators of Antibiotics)

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