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Molecules
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Chemical Design and Synthesis of Antimicrobial Drugs
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Chemical Design and Synthesis of Antimicrobial Drugs

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 31 August 2025 | Viewed by 2603

Special Issue Editors

Dr. Ma Su

E-Mail Website
Guest Editor
College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
Interests: drug discovery; medicinal chemistry; antimicrobial drugs; small-molecule inhibitors; peptidomimetics; stapled peptides
Dr. Diana I.S.P. Resende

E-Mail Website
Guest Editor
1. LQOF-Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Rua de Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal
2. CIIMAR-Interdisciplinary Centre of Marine and Environmental Research, Terminal de Cruzeiros do Porto de Leixões, 4450-208 Matosinhos, Portugal
3. ICBAS-School of Medicine and Biomedical Sciences, University of Porto, Rua de Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal
Interests: pharmaceuticals; chemical sciences; organic chemistry

Special Issue Information

Dear Colleagues,

The development of antimicrobial drugs with novel structures and clear mechanisms of action that are active against drug-resistant bacteria has become urgent; this is due to the rise of bacterial drug resistance and the need to safeguard human health. To combat antimicrobial resistance, the WHO published a list of “ESKAPE” pathogens that pose the greatest threat to human health in 2017; in order, these are Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.

Researchers have thus attempted to uncover the mystery of bacterial resistance and develop more convenient and effective antibacterial strategies. This Special Issue provides up-to-date research and perspectives on the discovery, rational design, and chemical, pharmacological, in vitro and clinical properties of natural and synthetic antimicrobial agents, in order to understand the relationship between their molecular structure and biological activity or mode of action. The scope of this Special Issue includes the following:

The design, synthesis, and biological evaluation of novel biologically active antimicrobial compounds.

The molecular modification of reported series that lead to a significantly enhanced understanding of their structure–activity relationships (SAR).

Computational studies that provide fresh insight into the SAR of compound series that are of current general interest, or the analysis of other available data that subsequently advance medicinal chemistry knowledge.

The effect of the molecular structure on the distribution, pharmacokinetics, and metabolic transformation of biologically active compounds. This may include the design, synthesis, and evaluation of novel types of prodrugs.

Dr. Ma Su
Dr. Diana I.S.P. Resende
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • antimicrobial drugs
  • rational design
  • drug resistance
  • ESKAPE pathogens
  • structure–activity relationship
  • advanced skeleton

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Published Papers (3 papers)

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Research

25 pages, 3867 KiB  
Article
Amino Acid Substitutions in Bacteriocin Lactolisterin BU Reveal Functional Domains Involved in Biological Activity Against Staphylococcus aureus
by Lazar Gardijan, Milka Malešević, Miroslav Dinić, Aleksandar Pavić, Nikola Plačkić, Goran Jovanović and Milan Kojić
Molecules 2025, 30(15), 3134; https://doi.org/10.3390/molecules30153134 - 26 Jul 2025
Viewed by 586
Abstract
The emergence of multidrug-resistant pathogens has driven the development of novel antimicrobial peptides (AMPs) as therapeutic alternatives. Lactolisterin LBU (LBU) is a bacteriocin with promising activity against Gram-positive bacteria, including Staphylococcus aureus. In this study, we designed and evaluated a panel of [...] Read more.
The emergence of multidrug-resistant pathogens has driven the development of novel antimicrobial peptides (AMPs) as therapeutic alternatives. Lactolisterin LBU (LBU) is a bacteriocin with promising activity against Gram-positive bacteria, including Staphylococcus aureus. In this study, we designed and evaluated a panel of amino acid variants of LBU to investigate domain–activity relationships and improve activity. Peptides were commercially synthesized, and their effect was evaluated for minimal inhibitory concentration (MIC), minimal bactericidal concentration (MBC), hemolytic activity, cytotoxicity, in vivo toxicity, and virulence modulation. AlphaFold3 structural prediction of LBU revealed a four-helix topology with amphipathic and hydrophobic segments. Helical wheel projections identified helices I and IV as amphipathic, suggesting their potential involvement in membrane interaction and activity. Glycine-to-alanine substitutions at helix I markedly increased antimicrobial activity but altered toxicity profiles. In contrast, changes at helix junctions and kinks reduced antimicrobial activity. We also showed differential regulation of virulence genes upon sub-MIC treatment. Overall, rational substitution enabled identification of residues critical for activity and toxicity, providing insights into therapeutic tuning of lactolisterin-based peptides. Full article
(This article belongs to the Special Issue Chemical Design and Synthesis of Antimicrobial Drugs)
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15 pages, 586 KiB  
Article
Antifouling Properties of N,N′-Dialkylated Tetraazamacrocyclic Polyamines and Their Metal Complexes
by Mathieu Berchel, Dorsaf Malouch, Maryline Beyler, Maryline Fauchon, Yannick Toueix, Claire Hellio and Paul-Alain Jaffrès
Molecules 2025, 30(11), 2368; https://doi.org/10.3390/molecules30112368 - 29 May 2025
Cited by 1 | Viewed by 345
Abstract
The prevention of biofouling (biological fouling) became a major economic and environmental issue. In the present study, we designed a series of four cyclam and cyclen derivatives with a modulation of their lipophilicity by introducing either two benzyl (Bn) groups or two tetradecyl [...] Read more.
The prevention of biofouling (biological fouling) became a major economic and environmental issue. In the present study, we designed a series of four cyclam and cyclen derivatives with a modulation of their lipophilicity by introducing either two benzyl (Bn) groups or two tetradecyl (C14) chains in the structure to produce (Cyclam(Bn)2, Cyclam(C14)2, Cyclen(Bn)2 and Cyclen(C14)2). Additionally, copper (Cu) and zinc (Zn) complexes of each compound were prepared and evaluated as potential antifouling candidates against two models of Vibrio species (V. natriegens and V. aestuarianus). The results highlight that no significant antifouling activity was measured for the metal free polyazamacrocyclic derivatives. However, for the metal complexes, the nature of the cation (Cu2+ or Zn2+) modulates both the growth and adhesion capacities of the two bacteria. Overall, in most cases, Zn complexes showed better activity than the Cu complexes, revealing the importance of the metal cation. Moreover, in the cyclam series, the anti-adhesion properties could be linked to a biocidal effect while a full anti-adhesion activity was observed in the cyclen series. Full article
(This article belongs to the Special Issue Chemical Design and Synthesis of Antimicrobial Drugs)
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22 pages, 5706 KiB  
Article
Antibiofilm Activities of Tritrpticin Analogs Against Pathogenic Pseudomonas aeruginosa PA01 Strains
by Gopal Ramamourthy, Hiroaki Ishida and Hans J. Vogel
Molecules 2025, 30(4), 826; https://doi.org/10.3390/molecules30040826 - 11 Feb 2025
Viewed by 968
Abstract
In our previous work, we showed that short antimicrobial hexapeptides (AMPs) containing three Trp and three Arg residues had a potent antibiofilm activity against a pathogenic Gram-positive Staphylococcus aureus MRSA strain. However, the activity of these hexapeptides against a Gram-negative Pseudomonas aeruginosa PA01 [...] Read more.
In our previous work, we showed that short antimicrobial hexapeptides (AMPs) containing three Trp and three Arg residues had a potent antibiofilm activity against a pathogenic Gram-positive Staphylococcus aureus MRSA strain. However, the activity of these hexapeptides against a Gram-negative Pseudomonas aeruginosa PA01 strain was relatively poor. Herein, we tested the longer 13-residue synthetic AMP tritrpticin-NH2 (Tritrp) and several of its analogs as potential antibiofilm agents that can prevent biofilm formation (MBIC) and/or cause biofilm dissolution (MBEC) for two P. aeruginosa PA01 strains, one of which expressed the GFP protein. Tritrp, a porcine cathelicidin, is currently the only known naturally occurring cationic AMP that has three Trp in sequence (WWW), a feature that was found to be important in our previous study. Our results show that several Tritrp analogs were effective. In particular, analogs with Pro substitutions that had altered peptide backbone structures compared to the naturally occurring amphipathic two-turn structure showed more potent MBIC and MBEC antibiofilm activities. Selectivity of the peptides towards P. aeruginosa could be improved by introducing the non-proteinogenic amino acid 2,3-diaminopropionic acid, rather than Arg or Lys, as the positively charged residues. Using 1H NMR spectroscopy, we also reinvestigated the role of the two Pro residues in cis–trans isomerism of the peptide in aqueous solution. Overall, our results show that the WWW motif embedded in longer cationic AMPs has considerable potential to combat biofilm formation in pathogenic Gram-negative strains. Full article
(This article belongs to the Special Issue Chemical Design and Synthesis of Antimicrobial Drugs)
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