AlkylGuanidino Ureas, from a Serendipitous Discovery to a Rational Design: Innovative Membrane-Active Antibacterial Agents †
1
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro, 2, IT-53100 Siena, Italy
2
Dipartimento di Biotecnologie Mediche, University of Siena, Viale Bracci 16, IT-53100 Siena, Italy
3
Lead Discovery Siena s.r.l., Via Vittorio Alfieri 31, IT-53019 Castelnuovo Berardenga, Italy
4
Laboratoire de Bactériologie Moléculaire, Centre d′Ingénierie des Protéines—UR InBioS, University of Liège, Allée du six Août 11, 4000 Liège, Belgium
5
Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, BioLife Science Building, Suite 333, 1900 North 12th Street, Philadelphia, PA 19122, USA
*
Author to whom correspondence should be addressed.
†
Presented at the 2nd International Electronic Conference on Antibiotics—Drugs for Superbugs: Antibiotic Discovery, Modes of Action and Mechanisms of Resistance, 15–30 June 2022; Available online: https://eca2022.sciforum.net/ .
‡
Present address: Department of Pharmacy, “G. d’Annunzio” University of Chieti-Pescara, Via dei Vestini, 32, IT-66100 Chieti, Italy.
§
Prof. M. Botta (1950–2019).
Med. Sci. Forum 2022, 12(1), 40; https://doi.org/10.3390/eca2022-12756
Published: 23 June 2022
(This article belongs to the Proceedings of The 2nd International Electronic Conference on Antibiotics—Drugs for Superbugs: Antibiotic Discovery, Modes of Action and Mechanisms of Resistance)
The relentless and global rise of bacterial resistance is undoubtedly one of the most worrisome Public Health issues. Currently available antibiotics are becoming increasingly ineffective for the treatment of infections caused by extensively-drug resistant (XDR) strains, prompting a challenging discovery and development of novel antibiotics, including with either innovative chemical scaffolds or Modes of Action (MoAs).
We recently reported the serendipitous discovery of AlkylGuanidino Ureas (AGUs), amphipathic compounds exerting a potent and broad-spectrum bactericidal activity [1,2,3,4]. Briefly, a bis-guanidino amine (1, Figure 1) [5] was found to spontaneously generate a multi-component mixture including oligomers through a hypothesized carbon dioxide capture. A multidisciplinary approach of in-depth MS studies, design, and synthesis led to the identification of tetrasubstituted guanidino urea (2, Figure 1) exhibiting Minimal Inhibitory Concentration (MIC) values ranging from 0.5 to 16 μg/mL on both Gram-positive and Gram-negative bacterial species, including on antibiotic-resistant clinical isolates with XDR phenotypes [2]. We subsequently designed and synthesized a library of analogues of 2 by modifying the length of the alkyl spacers and the N-guanidino substitutions, allowing a better understanding of some interesting structure-activity relationships (SARs) of AGUs [3].
Further insight into the AGUs MoA was obtained through the rational design of AGU derivatives via a molecular simplification approach, one of which (3, Figure 1) emerged among others for its potent antibacterial activity (MICs range 0.5–16 μg/mL). In addition, we developed a modified Parallel Artificial Membrane Permeability Assay (PAMPA) by using bacterial phospholipids-endowed bilayers and poorly permeable probes to assess the ability of AGUs to disrupt the bilayers and affect their permeability. Furthermore, molecular dynamics on simulated bacterial bilayers highlighted the strong interaction of AGUs with the membranes in a “carpet-like” manner. However, in cellulo assays with propidium iodide and SYTO 9 validated the model-based experiments and confirmed the AGUs membrane-targeting MoA [6]. In summary, the AGUs class has proven to be worthy of interest in the Med Chem frame for its innovative chemical structure and potent antibacterial activity and could serve as a basis for the optimization of new, much-needed, antibacterials.
Supplementary Materials
The following are available online at https://www.mdpi.com/article/10.3390/eca2022-12756/s1.
Author Contributions
Supervision, project administration: J.-D.D. and M.B.; conceptualization, investigation: I.D., J.-D.D. and M.B. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no external funding.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Not applicable.
Acknowledgments
We are grateful to all the collaborators who worked on the whole project: D. Deodato, C. Pasero, C. Ardino for syntheses; F. De Luca and F. Sannio for microbiology and antibacterial susceptibility testing; P. Visca for microbiological investigation; G. Poli for computational studies; C. Zamperini and E. Dreassi for analytical studies: Lead Discovery Siena s.r.l. for financial support.
Conflicts of Interest
The authors declare no conflict of interest.
References
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Figure 1.
Representative compounds of the AGUs class: monomer 1, symmetric dimer 2, and simplified urea 3. Fragments of the compounds are highlighted in different colors: in cyan the cyclopropylmethyl guanidino arm, in green the unsubstituted guanidino arm, and in yellow the carbonyl group composing the urea function. The arrows indicate the complex advancement of the research project on AGUs.
Figure 1.
Representative compounds of the AGUs class: monomer 1, symmetric dimer 2, and simplified urea 3. Fragments of the compounds are highlighted in different colors: in cyan the cyclopropylmethyl guanidino arm, in green the unsubstituted guanidino arm, and in yellow the carbonyl group composing the urea function. The arrows indicate the complex advancement of the research project on AGUs.
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MDPI and ACS Style
D’Agostino, I.; Docquier, J.-D.; Botta, M. AlkylGuanidino Ureas, from a Serendipitous Discovery to a Rational Design: Innovative Membrane-Active Antibacterial Agents. Med. Sci. Forum 2022, 12, 40. https://doi.org/10.3390/eca2022-12756
AMA Style
D’Agostino I, Docquier J-D, Botta M. AlkylGuanidino Ureas, from a Serendipitous Discovery to a Rational Design: Innovative Membrane-Active Antibacterial Agents. Medical Sciences Forum. 2022; 12(1):40. https://doi.org/10.3390/eca2022-12756
Chicago/Turabian StyleD’Agostino, Ilaria, Jean-Denis Docquier, and Maurizio Botta. 2022. "AlkylGuanidino Ureas, from a Serendipitous Discovery to a Rational Design: Innovative Membrane-Active Antibacterial Agents" Medical Sciences Forum 12, no. 1: 40. https://doi.org/10.3390/eca2022-12756
