Next Article in Journal
The Role of Adenosine A1 and A2a Receptors in Cerebral Blood Vessel Reactivity of Sprague Dawley Rats Exposed to Hyperbaric Oxygenation
Next Article in Special Issue
Photophysical Properties of 1,3-Diphenylisobenzofuran as a Sensitizer and Its Reaction with O2
Previous Article in Journal
Structure-Based Design of Small-Molecule Inhibitors of Human Interleukin-6
Previous Article in Special Issue
Understanding Bio-Orthogonal Strain-Driven Sydnone Cycloadditions: Data-Assisted Profiles and the Search for Linear Relationships
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 30
Issue 14
10.3390/molecules30142920
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

In Search of New Drugs: Elucidating the Activity of Structurally Similar Potential Antibiotics Using Molecular Modelling

by
Natalina Makieieva
1,*,
Teobald Kupka
1,*,
Piotr Lodowski
2,
Radosław Balwierz
1,
Katarzyna Kasperkiewicz
3,
Adam Byrski
4,
Roksolana Konechna
5 and
Vira Lubenets
5
1
Faculty of Chemistry and Pharmacy, University of Opole, Oleska 48, 45-052 Opole, Poland
2
Institute of Chemistry, University of Silesia in Katowice, Szkolna 9, 40-006 Katowice, Poland
3
Faculty of Natural Sciences, Institute of Biology, Biotechnology and Environmental Protection, University of Silesia in Katowice, Jagiellonska 28, 40-032 Katowice, Poland
4
Institute of Metallurgy and Materials Science, Polish Academy of Sciences, Reymonta 25, 30-059 Cracow, Poland
5
Department of Technology of Biologically Active Substances, Pharmacy and Biotechnology of Lviv Polytechnic National University, S. Bandery 12, 79000 Lviv, Ukraine
*
Authors to whom correspondence should be addressed.
Molecules 2025, 30(14), 2920; https://doi.org/10.3390/molecules30142920
Submission received: 9 June 2025 / Revised: 27 June 2025 / Accepted: 8 July 2025 / Published: 10 July 2025
(This article belongs to the Special Issue Quantum Chemical Calculations of Molecular Reaction Processes, 2nd Edition)
Browse Figures
Versions Notes

Abstract

The global problem of antibiotic resistance leads to the necessity for drug improvement and discovery. Natural and synthetic sulfur-containing compounds have been known as antibiotics for many years. In the current study, we demonstrated an antibacterial activity of three new thiosulfonates: S-ethyl 4-aminobenzene-1-sulfonothioate (1), S-methyl 4-acetamidobenzene-1-sulfonothioate (2), and S-ethyl 4-acetamidobenzene-1-sulfonothioate (3). Their activities were studied on two model Gram-positive and Gram-negative bacteria strains: Staphylococcus aureus ATTC 6538P and Escherichia coli ATTC 8739, respectively. According to the literature data, we proposed a general mechanism of 1−3 biochemical actions. To analyze its feasibility, theoretical studies using density functional theory (DFT) were performed. The obtained results demonstrate a direct correlation between some NBO parameters and the S-S bond energy of 1−3 with their activity against both studied bacterial strains. The obtained results could be helpful for future biomedical studies on the analyzed compounds and promote the further design of new S-containing antibiotics.

Graphical Abstract

1. Introduction

Antimicrobial resistance (AMR) has become one of the key healthcare issues in recent years. This condition occurs when populations of pathogenic microorganisms (bacteria, fungi, protozoa and viruses) in the host organism are resistant to the toxic effects of drugs. The reason for this phenomenon is primarily the excessive use of antibiotics without necessity, namely self-medication, erroneous prescription of medication or the demand for medication from medical personnel. Other factors include the excessive use of antibiotics in veterinary and agronomy, which leads to the accumulation of drugs in animal and plant foods consumed. In addition, insufficient purification of wastewater from antibiotics and their degradation by-products leads to the accumulation of drugs in the environment and their subsequent entry into plant, animal and human organisms [1,2,3]. Mortality due to human AMR is gradually increasing on the global stage. In 2019, 1.2 million deaths were registered, and according to World Health Organization (WHO) predictions, without modernization of antimicrobial therapies, we should expect about 10 million deaths per year [1]. This negative trend makes it necessary to analyze the existing antibiotic market in relation to the actual drugs’ effectiveness and to develop new medicines with an improved pharmacological profile.
One of the promising groups of antibiotics is -S-S- structural motive-containing organic compounds, namely disulfides, thiosulfinates and thiosulfonates (see the schematic formulas of each group in Figure 1).
The effectiveness of these compounds in the treatment of diseases of bacterial, fungal and viral origin has been known for a long time. The first representatives used in medical practice were metabolites of some Allium genus plants (see Figure 2) [4,5,6].
The activity of these compounds has been tested against a number of viruses [7], fungi [8], and Gram-positive and Gram-negative bacteria [5]. However, the development of microorganisms’ resistance to the action of traditional antibiotics leads to the limited spectrum of Allium metabolites use. For this reason, synergistic studies of the drugs’ action mechanisms and resistance to them are being conducted. A number of works describing the action of known antibiotics, the adaptation of microorganisms to them and the proposal of alternative medicines with a modified spectrum of action and more efficient destruction of the pathogen are presented [9,10,11,12,13]. For example, recent literature data suggest that the key mechanism of bacterial adaptation is modification of genetic material [14]. This leads to a change in the composition or targeted destruction of the cell membrane and, as a consequence, a decrease in drug permeability [14]. Another mechanism is a metabolic activity reduction leading to a decrease in the expression of antibiotic molecular targets. Bacterial metabolism modification could also provide new pathway formation, which leads to the modification or inactivation of drugs. Finally, an exchange of genetic material within the cells in biofilm provides the acquisition of resistance mechanisms in the colony [14]. To block the protective mechanisms and increase the permeability of the drug into the bacterial cell, the literature suggests the use of new classes of compounds: antibacterial proteins [15,16,17,18], metal nanoparticles [19,20], polymers [21,22,23] and others [24,25,26]. An increase in antibiotic activity has been observed when they are introduced into drug delivery systems, amplifying penetration into the bacterial cell [27,28,29]. Particular attention has been paid to the development of new synthetic compounds with an improved clinical profile. For example, D-modification of the amino acid sequence increases the antibacterial activity, safety and stability of the antibacterial proteins [30]. A strong structure–activity correlation was studied for a series of synthetic myrtucommulone analogues as potential inhibitors of DNA gyrase and topoisomerase IV [25]. Relatively little is known about the structural modification effect on the activity of organosulfur antibiotics, especially thiosulfonates. Only a few systematic studies present an attempt to establish the structure–activity relationship [31,32,33,34]. In the case of thiosulfonates, this is of particular importance, since in addition to their antibacterial properties, their anticancer potential has been noted [31,35,36,37].
The aim of our work was to expand the existing knowledge about the influence of structure on the antibacterial activity of thiosulfonates. We present data on the activity of three new derivatives of the thiosulfonate group: S-ethyl 4-aminobenzene-1-sulfonothioate (1), S-methyl 4-acetamidobenzene-1-sulfonothioate (2) and S-ethyl 4-acetamidobenzene-1-sulfonothioate (3) (see Figure 3). Microbiological tests were carried out on two model bacteria: Gram-positive Staphylococcus aureus ATTC 6538P and Gram-negative Escherichia coli ATTC 8739. In order to explain the different activities of structurally similar compounds, a systematic theoretical study was carried out.

2. Results and Discussion

Based on the obtained results (see Figure 4), it can be concluded that compound 1 has the highest activity against both Gram-positive and Gram-negative bacteria. It is also worth noting that substances 2 and 3 had similar activity against both S. aureus and E. coli. Derivative 1 significantly differed structurally from 2 and 3 (according to Figure 3, its amine end was not modified to amide), while 2 and 3 differed only in the length of the alkyl chain at the S-end.
The mechanism of thiosulfonates 1−3 antibacterial action is not described in the scientific literature. Moreover, limited data also describe the molecular mechanisms of other thiosulfonate antibiotic action [31,32,33,34]. However, some systematic works present the mechanisms of action of allicin and homolycin [38,39] (see Figure 5). It was described in [38,39] that both antibiotic molecular targets in bacterial cells are glutathione and cysteine residues of different peptide structures (enzymes, membrane peptides, etc.). As can be seen from Figure 5A, homolycin is a cyclic thiosulfonate. As a result of the first stage of its interactions with glutathione (GSH) or cysteine residues (Cys) of protein structures (in Figure 5, GSH/Cys are presented as R3-SH), it is reduced to cyclic thiosulfinate. This intermediate has a leading structural motif O=S-S-, similar to allicin. According to their structural similarity, it was supposed that further processing of reduction occurs in a similar way as in the case of allicin (Figure 5B). In contrast to 1−3 thiosulfonates, due to homolycin’s cyclic structure, there is no destruction of the drug molecule, but the closure of the disulfide bridge with simultaneous oxidation of GSH/Cys (R3S-SR3, Figure 5A). Based on the literature data, a theoretical mechanism of thiosulfonates 1−3’s antibacterial action is presented in Figure 6. To analyze the feasibility of this general mechanism, further systematic molecular modelling was performed.
During molecular modelling, certain parameters were calculated. First, the NBO charges and orbitals [40] were analyzed. According to the proposed reaction mechanism (see Figure 6), during biochemical transformations, the oxidized sulfur atom in the structure of 1−3 is subject to stepwise reduction. Therefore, the distribution of partial charges in the potential antibiotic molecules can serve as a key factor in the reaction rate and, consequently, biological activity. As can be seen from Figure 6, the -SO2-S- structural moiety is subject to modification to -SO-S- and further cleavage of the -S-S- bond. Therefore, it is assumed that an increase in the polarity of the -S=O bond will have a key effect in initiating the first and second stages of the reaction of 1−3 with biomolecules. As can be seen from Table 1, bond polarization decreases with decreasing antibacterial activity in 1−3. In addition, it can be noted that the difference in sulfur and two oxygen atoms NBO charges increases with decreasing activity. This indicates a decrease in the electron density on the oxygen atoms and, as a consequence, their lower ability to nucleophilic attack. This leads to a slowdown in the first stage of biochemical transformations of thiosulfonates 2 and 3. It is worth mentioning that for all analyzed thiosulfonates 1−3, a similar trend of NBO charges and orbital charges is observed in vacuum and in water (PCM). It can be noted that in water, the difference between sulfur and the two oxygen atoms NBO charges is not as significant as in vacuum. As can be seen from Table 1, in a polar environment, the negative charge on the oxygen atoms increases significantly. This can be explained by the effect of additional polarization of the environment, as well as by the improved prediction and stabilization of partial charges in the polar solvent. Similar values of the difference between sulfur and two oxygen atoms NBO charges in compounds 2 and 3 in a polar environment could be explained by their similar antibacterial activity (see Figure 4).
Analyzing the NBO orbitals (see Table 1), a similar growth of the -S=O1 bond polarization with antibacterial activity increase is observed both in vacuum and in water (PCM). After the first stage of reduction to transition products with the -SO-S- moiety, a similar dependence of the distribution of partial charges and the contribution of the NBO orbitals on biological activity is observed. As can be seen from Table 2, the smallest ΔNBO(S-O) value is obtained for the most active thiosulfinate 1. Moreover, the oxygen atom in 1 has the largest negative charge and, therefore, the largest electron density. Therefore, as in the case of thiosulfonate 1, the highest ability of its thiosulfinate to initiate a nucleophilic attack in reactions with glutathione or cysteine residues is expected. In the case of the NBO orbitals, the maximal polarization of the -S=O bond is also observed for the compound 1 transition product, which further indicates its highest reactivity (see Table 2). Moreover, the thiosulfinates’ NBO parameters calculated both in vacuum and in water correlate with the total activity of 1−3 (see Figure 4 and Table 2).
Analyzing the proposed reaction mechanism, it can be noted that the final stage involves the S-S bond cleavage in the transition products of 1−3. Based on this, it can be assumed that the activity of potential antibiotics will correlate with the S-S bond energy. As can be seen from Table 3, the lowest value of the S-S bond dissociation energy was observed in the case of compound 1 thiosulfinate. The energy gradually increased for 2 and 3, with a decrease in antibacterial activity. It is worth noting that this correlation was obtained both in the case of the dissociation energy with and without the ZPE correction in vacuum and in water (PCM). Based on this, it can be assumed that the S-S bond energy plays a significant role in the process of biochemical reactions of 1−3 with glutathione and cysteine residues. According to the II part of the proposed general mechanism of biochemical action (see Figure 6), it can be suspected that the weakening of S-S leads to an increase in the reactivity of compound 1 toward molecular targets (glutathione and cysteine residues). This may lead to acceleration and enhancement of the antibacterial action of compound 1 against Gram-negative and Gram-positive bacteria. However, this assumption requires additional confirmation by systematic theoretical and experimental studies.
To summarize, a direct correlation between the NBO charges of oxygen atoms in the S=O motif and the polarization of this bond, as well as the energy of the S-S bond dissociation with the compounds 1−3, antibacterial activity was observed. It is worth noting that the correlation was obtained in both the gas phase and water (PCM) calculations. The results partially confirm the proposed general mechanism of biochemical transformations of thiosulfonates 1−3 (Figure 6) in Gram-positive and Gram-negative bacteria cells. It can be stated that although the analyzed compounds are structurally similar, they exhibit different abilities for nucleophilic attacks on molecular targets in the bacteria cells. However, a detailed description of compounds 1−3 transformation mechanisms at the molecular level requires additional theoretical and experimental studies. They will be presented in further works.

3. Materials and Methods

3.1. Synthesis and Purification

The procedure of the synthesis of all analyzed thiosulfonates 1–3 has been presented previously [41,42]. The purity of the obtained samples was determined based on data from a number of analytical methods. Reaction product purity was determined using thin-layer chromatography (TLC) on “Silufol UV 254” plates. The melting points were determined without correction in open capillary tubes. Liquid chromatograph-mass spectrometry (LC-MS) spectra were also recorded using an Agilent 110\DAD\HSD\VLG 119,562 apparatus (Agilent, Headquarters, Santa Clara, CA, USA). Ionization by electrospray was performed under atmospheric pressure (70 eV). Elemental analysis of the samples was performed using the Perkin Elmer CHN-Analyzer series 2400 (Perkin Elmer, Waltham, MA, USA). Complex spectrometric analysis was also performed. IR spectra were measured using a Thermo Nicolet spectrometer (Nexus Analytics, Madison, WI, USA) (see Figures S3 and S6). The 1H and 13C NMR spectra were recorded using an Ultrashield Bruker spectrometer (400 MHz) (Bruker Optik GmbH, Ettlingen, Germany) in DMSO-d6. The chemical shifts were reported relative to TMS (see Figure S1, S2, S4 and S5).

3.2. Antimicrobial Activity

3.2.1. Bacterial Strains and Tested Compounds Solutions

Antibacterial activity of 1−3 was tested on two bacterial strains: Escherichia coli ATTC 8739 and Staphylococcus aureus ATTC 6538P as model Gram-positive and Gram-negative bacteria, respectively. The strains were taken from the collection of the Institute of Biology, Biotechnology and Environmental Protection (University of Silesia in Katowice). Prior to tests, microorganisms were cultivated overnight at 36  ±  1 °C using Nutrient broth (Merck Millipore, Burlington, MA, USA; for E. coli) and Tryptic soy broth (Merck Millipore, Burlington, MA, USA; for S. aureus) media, previously sterilized in an autoclave (15 min, 121 °C). Each of the 1−3 tested compounds was dissolved in phosphate-buffered saline (PBS) at pH 7.4. The concentration of each final solution was 100 mg/mL. This concentration was chosen because the aim of the study was to determine compounds’ potential antibacterial properties without minimum inhibitory concentration measurements.

3.2.2. Disk Diffusion Method

The antimicrobial activity was analyzed using the disc diffusion test on Mueller–Hinton agar plates. The inoculum was prepared as a suspension with a turbidity of 0.5 on the McFarland scale (approximately optical density (OD) at 600  nm is 0.06), which was achieved by diluting overnight cultures in PBS. The bacteria were seeded on the Mueller–Hinton agar using the turf method. Sterile paper discs of 6 mm diameter were partially immersed in the tested 1−3 compounds solutions and control (PBS) and subsequently applied to the plates in three replicates. The plates were inverted and incubated for 24 h at 37 °C in a humidified (~90%) atmosphere. The diameter of the bright zones was then measured as a proportional value to the sensitivity of the tested strain to a given compound. The results are presented as the mean of three replicates.

3.2.3. Statistical Analysis

A parametric analysis of variance ANOVA was used to compare microbial inhibition zone values. For post hoc multiple comparisons, Fisher’s LSD test was used. In all analyses and statistical tests performed, a significance level of α = 0.05 was adopted.

3.3. Theoretical Studies

All calculations were performed using Gaussian 16 C.01 software [43]. The first step was the structural optimization. To analyze the influence of the environment polarity on the chemical activity of 1−3, optimization and all theoretical parameters were calculated in the gas phase and water using the Polarizable Continuum Model (PCM) [44]. The structure optimization was performed for neutral forms of 1−3 thiosulfonates and thiosulfinates (geometries are presented in Tables S1–S4). The criterion for obtaining the energetically equilibrium structure was the absence of negative values of harmonic vibrational frequencies. All calculations were performed using the hybrid density functional of Becke-Lee-Yang-Parr B3LYP [45,46,47] with Grimm’s empirical correction for dispersion (D3BJ) [48]. This method demonstrated acceptable accuracy in calculating the structural, spectroscopic and energy parameters of small and medium-sized molecules [49,50]. In order to obtain all structural, energy and NBO values with satisfactory accuracy, the Pople’s 6-311++G** basis set was used [51]. The S-S bond dissociation was analyzed as homolytic fission. This mechanism was used based on the analysis of the NBO orbitals, which indicate the covalence of the S-S moiety in all analyzed thiosulfinates (see Table A1 in the Appendix A). Bond dissociation energies in kcal/mol were calculated according to the following formula:
∆ E R 1 S − S R 2 = E R 1 S + E R 2 S − E R 1 S − S R 2   ∗   627.509 ,
where ∆ E R 1 S − S R 2 is electronic energy without or with zero-point energy (ZPE) of S-S bond dissociation, while E are electronic energies without or with zero-point energies (ZPE) of the studied compound or its fragments.

4. Conclusions

In this work, a comparative characteristic of the biological activity of three new thiosulfinates is presented. The antibacterial potential of this group of compounds is described in the literature. However, their mechanism of action at the molecular level has not been studied in detail. In addition, very little data are presented on the dependence of thiosulfonate activity on structural modification. In this work, the activity of three structurally similar thiosulfonates, S-ethyl 4-aminobenzene-1-sulfonothioate (1), S-methyl 4-acetamidobenzene-1-sulfonothioate (2) and S-ethyl 4-acetamidobenzene-1-sulfonothioate (3) against Escherichia coli ATTC 8739 as a model Gram-negative bacteria and Staphylococcus aureus ATTC 6538P as a model Gram-positive bacteria, was analyzed. A significantly different high activity of compound 1 against both bacterial species is noted. At the same time, it is noted that compounds 2 and 3’s activities were quite similar. To explain the relationship between structure and activity, a potential general mechanism of antibacterial activity was proposed based on the available literature. To determine its feasibility, molecular modelling of some parameters of compounds 1−3 was performed. A direct correlation between the charge on the oxygen atom and the polarization of the -S=O bond with the overall activity of compounds 1−3 was noted. In addition, a connection between the energy of the S-S bond of the 1−3 transition products and the overall activity against E. coli and S. aureus was noted. Theoretical data demonstrate the possibility of the proposed general mechanism. However, additional experimental and theoretical studies are needed to describe the mechanism of antibacterial action at the molecular level in detail.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules30142920/s1.

Author Contributions

Conceptualization, N.M., T.K. and P.L.; methodology, N.M., T.K. and P.L.; software, N.M.; validation, T.K. and P.L.; formal analysis, T.K. and R.B.; investigation, N.M., R.B., K.K., A.B., R.K. and V.L.; resources, R.K., V.L. and K.K.; data curation, N.M., R.B., K.K. and A.B.; writing—original draft preparation, N.M.; writing—review and editing, T.K., P.L. and R.B.; visualization, N.M. and R.B.; supervision, T.K.; project administration, T.K.; funding acquisition, V.L. 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

Data is contained within the article.

Acknowledgments

Created using resources provided by Wroclaw Centre for Networking and Supercomputing (http://wcss.pl). Grant no. hpc-titanium-1721124296.

Conflicts of Interest

The authors declare no conflicts of interest.

Appendix A

Table A1. NBO orbitals of S-S bonds in thiosulfinates 1−3, calculated in the gas phase and water (PCM).
Table A1. NBO orbitals of S-S bonds in thiosulfinates 1−3, calculated in the gas phase and water (PCM).
CompoundNBO Orbitals–Gas phase, %NBO Orbitals–Water (PCM), %
S(O)SS(O)S
150.1449.8650.0349.97
249.7950.2150.2049.80
349.3050.7049.5950.41

References

  1. Schurer, M.; Patel, R.; van Keep, M.; Horgan, J.; Matthijsse, S.; Madin-Warburton, M. Recent Advances in Addressing the Market Failure of New Antimicrobials: Learnings from NICE’s Subscription-Style Payment Model. Front. Med. Technol. 2023, 5, 1010247. [Google Scholar] [CrossRef]
  2. Ai, T.; Yao, S.; Yu, Y.; Peng, K.; Jin, L.; Zhu, X.; Zhou, H.; Huang, J.; Sun, J.; Zhu, L. Transformation Process and Phytotoxicity of Sulfamethoxazole and N4-Acetyl-Sulfamethoxazole in Rice. Sci. Total Environ. 2024, 918, 170857. [Google Scholar] [CrossRef] [PubMed]
  3. Huynh, K.; Reinhold, D. Metabolism of Sulfamethoxazole by the Model Plant Arabidopsis Thaliana. Environ. Sci. Technol. 2019, 53, 4901–4911. [Google Scholar] [CrossRef]
  4. Blume, L.; Long, T.E.; Turos, E. Applications and Opportunities in Using Disulfides, Thiosulfinates, and Thiosulfonates as Antibacterials. Int. J. Mol. Sci. 2023, 24, 8659. [Google Scholar] [CrossRef] [PubMed]
  5. Bhatwalkar, S.B.; Mondal, R.; Krishna, S.B.N.; Adam, J.K.; Govender, P.; Anupam, R. Antibacterial Properties of Organosulfur Compounds of Garlic (Allium sativum). Front. Microbiol. 2021, 12, 613077. [Google Scholar] [CrossRef]
  6. Seo, K.I.; Moon, Y.H.; Choi, S.U.; Park, K.H. Antibacterial Activity of S-Methyl Methanethiosulfinate and S-Methyl 2-Propene-1-Thiosulfinate from Chinese Chive toward Escherichia Coli O157:H7. Biosci. Biotechnol. Biochem. 2001, 65, 966–968. [Google Scholar] [CrossRef] [PubMed]
  7. Bandara, H.M.S.K.H.; Alakolanga, A.G.A.W.; Amarasinghe, N.R.; Adikaram, N.K.B.; Jayasinghe, L.; Fujimoto, Y. Antiviral Activities of Some Traditional Medicinal Plants of Sri Lanka. Curr. Tradit. Med. 2023, 9, 25–38. [Google Scholar] [CrossRef]
  8. Marchese, A.; Barbieri, R.; Sanches-Silva, A.; Daglia, M.; Nabavi, S.F.; Jafari, N.J.; Izadi, M.; Ajami, M.; Nabavi, S.M. Antifungal and Antibacterial Activities of Allicin: A Review. Trends Food Sci. Technol. 2016, 52, 49–56. [Google Scholar] [CrossRef]
  9. Correia, S.; Poeta, P.; Hébraud, M.; Capelo, J.L.; Igrejas, G. Mechanisms of Quinolone Action and Resistance: Where Do We Stand? J. Med. Microbiol. 2017, 66, 551–559. [Google Scholar] [CrossRef]
  10. Floss, H.G.; Yu, T.-W. RifamycinMode of Action, Resistance, and Biosynthesis. Chem. Rev. 2005, 105, 621–632. [Google Scholar] [CrossRef]
  11. Beyer, D.; Pepper, K. The Streptogramin Antibiotics: Update on Their Mechanism of Action. Expert Opin. Investig. Drugs 1998, 7, 591–599. [Google Scholar] [CrossRef] [PubMed]
  12. Sköld, O. Sulfonamide Resistance: Mechanisms and Trends. Drug Resist. Updat. 2000, 3, 155–160. [Google Scholar] [CrossRef] [PubMed]
  13. Markley, J.L.; Wencewicz, T.A. Tetracycline-Inactivating Enzymes. Front. Microbiol. 2018, 9, 1058. [Google Scholar] [CrossRef] [PubMed]
  14. Darby, E.M.; Trampari, E.; Siasat, P.; Gaya, M.S.; Alav, I.; Webber, M.A.; Blair, J.M.A. Molecular Mechanisms of Antibiotic Resistance Revisited. Nat. Rev. Microbiol. 2023, 21, 280–295. [Google Scholar] [CrossRef]
  15. Kumari, A.; Mathur, G.; Sharma, G. Antimicrobial Peptides in Tuberculosis: Insights into the Immunomodulatory Mechanisms. Chem. Biol. Lett. 2025, 12, 1253. [Google Scholar] [CrossRef]
  16. Basabe-Tuero, L.; Ayala, L.; Espinosa, I.; Machín, Y.; Coto, L.; Duarte, C.; Piloto, S.; Morales, A.; Rodrigo, O.; Diago, D.; et al. Oreochromicin-2 Shows Antimicrobial and Immunostimulant Effect against Respiratory Pathogens in Pigs. Res. Vet. Sci. 2025, 184, 105523. [Google Scholar] [CrossRef]
  17. Stevens, M.T.; Hawkins, P.M.E.; Wang, T.; Payne, R.J.; Britton, W.J. Analogue of the Natural Product Ecumicin Causes Sustained Growth Inhibition of Mycobacterium tuberculosis under Multiple Growth Conditions. Tuberculosis 2025, 151, 102594. [Google Scholar] [CrossRef]
  18. León Madrazo, A.; Quintana Owen, P.; Pérez Mendoza, G.; Segura Campos, M.R. Chia Derived Peptides Affecting Bacterial Membrane and DNA: Insights from Staphylococcus Aureus and Escherichia Coli Studies. Plant Foods Hum. Nutr. 2024, 80, 22. [Google Scholar] [CrossRef]
  19. Dogheim, G.M.; Alazhary, N.N.; Elbadry, O.A.; Amralla, M.T. Biosynthesized Silver Nanoparticles as an Environmental-Friendly Antibacterial Nanosystem against Methicillin-Resistant Staphylococcus Aureus. Inorg. Chem. Commun. 2025, 173, 113809. [Google Scholar] [CrossRef]
  20. Ghadimi, N.; Asadpour, L.; Mokhtary, M. Enhanced Antimicrobial, Anti-Biofilm, and Efflux Pump Inhibitory Effects of Ursolic Acid-Conjugated Magnetic Nanoparticles against Clinical Isolates of Multidrug-Resistant Pseudomonas aeruginosa. Microb. Pathog. 2025, 199, 107241. [Google Scholar] [CrossRef]
  21. Si, Z.; Sun, Y.; Tan, C.; Ooi, Y.J.; Li, M.; Raju, C.; Shubi, J.; Gan, Y.-H.; Zhu, Y.; Li, P.; et al. A Cationic Main-Chain Poly(Carbonate-Imidazolium) Potent against Mycobacterium abscessus and Other Resistant Bacteria in Mice. Biomaterials 2025, 316, 123003. [Google Scholar] [CrossRef] [PubMed]
  22. Nabawy, A.; Chattopadhyay, A.N.; Makabenta, J.M.V.; Hassan, M.A.; Yang, J.; Park, J.; Jiang, M.; Jeon, T.; Im, J.; Rotello, V.M. Cationic Conjugated Polymers with Tunable Hydrophobicity for Efficient Treatment of Multidrug-Resistant Wound Biofilm Infections. Biomaterials 2025, 316, 123015. [Google Scholar] [CrossRef] [PubMed]
  23. Cong, Z.; Yan, Z.; Xiao, X.; Liu, L.; Luo, Z.; Zou, J.; Chen, M.; Wu, Y.; Zhou, M.; Liu, R. Peptide-Mimicking Poly(2-Oxazoline) Displaying Potent Antibacterial and Antibiofilm Activities against Multidrug-Resistant Gram-Positive Pathogenic Bacteria. J. Mater. Sci. Technol. 2025, 214, 233–244. [Google Scholar] [CrossRef]
  24. Shakir, M.; Ali, A.; Lakshmi, S.; Garg, M.; Abdulhameed Almuqdadi, H.T.; Irfan, I.; Kamthan, M.; Joshi, M.C.; Javed, S.; Rawat, D.S.; et al. Synthesis and Mechanistic Studies of 4-Aminoquinoline-Isatin Molecular Hybrids and Schiff’s Bases as Promising Antimicrobial Agents. Eur. J. Med. Chem. 2025, 283, 117127. [Google Scholar] [CrossRef] [PubMed]
  25. Yang, H.; Li, J.; Wang, B.-L.; Yang, X.-Y.; Zhang, Y. Discovery, Synthesis, and Antibacterial Activity of Novel Myrtucommulone Analogs as Inhibitors of DNA Gyrase and Topoisomerase IV. Eur. J. Med. Chem. 2025, 283, 117138. [Google Scholar] [CrossRef]
  26. Lu, X.; Xu, X.; Ding, Y.; Gong, X.; Ming, L.; Dai, X.; Gu, C.; Wang, J.; Zhao, J.; Gao, M.; et al. Discovery and Optimization of Tetrahydroacridine Derivatives as a Novel Class of Antibiotics against Multidrug-Resistant Gram-Positive Pathogens by Targeting Type I Signal Peptidase and Disrupting Bacterial Membrane. Eur. J. Med. Chem. 2025, 283, 117101. [Google Scholar] [CrossRef] [PubMed]
  27. Ahmed, M.S.; Hussein, N.N.; Sulaiman, G.M.; Khan, R.A.; Mohammed, H.A. Piperacillin-Loaded Amine Functionalized Mesoporous Silica Nanoparticles: A New Frontier in Combating Multidrug-Resistant Pathogenic Bacteria through Value-Added Piperacillin Antibiotic. J. Drug Deliv. Sci. Technol. 2025, 105, 106580. [Google Scholar] [CrossRef]
  28. Fesendouz, S.A.; Hamishehkar, H.; Alizadeh, E.; Rahbarghazi, R.; Akbarzadeh, A.; Yousefi, S.; Milani, M. Bactericidal Activity and Biofilm Eradication of Pseudomonas Aeruginosa by Liposome-Encapsulated Piperacillin/Tazobactam. BioNanoScience 2024, 15, 87. [Google Scholar] [CrossRef]
  29. Liao, M.; Gong, H.; Ge, T.; Shen, K.; Campana, M.; McBain, A.J.; Wu, C.; Hu, X.; Lu, J.R. Probing Antimicrobial Synergy by Novel Lipopeptides Paired with Antibiotics. J. Colloid Interface Sci. 2025, 681, 82–94. [Google Scholar] [CrossRef]
  30. Li, B.; Liu, Y.; Yan, P.; Ouyang, X.; Ba, Z.; Wang, Y.; Yang, T.; Yu, Z.; Ren, B.; Zhong, C.; et al. The Novel β-Hairpin Antimicrobial Peptide D-G(RF)3 Demonstrates Exceptional Antibacterial Efficacy. Eur. J. Med. Chem. 2025, 283, 117149. [Google Scholar] [CrossRef]
  31. Ghilardi, A.F.; Yaaghubi, E.; Ferreira, R.B.; Law, M.E.; Yang, Y.; Davis, B.J.; Schilson, C.M.; Ghiviriga, I.; Roitberg, A.E.; Law, B.K.; et al. Anticancer Agents Derived from Cyclic Thiosulfonates: Structure-Reactivity and Structure-Activity Relationships. ChemMedChem 2022, 17, e202200165. [Google Scholar] [CrossRef] [PubMed]
  32. Kato, T.; Lim, B.; Cheng, Y.; Pham, A.-T.; Maynard, J.; Moreau, D.; Poblador-Bahamonde, A.I.; Sakai, N.; Matile, S. Cyclic Thiosulfonates for Thiol-Mediated Uptake: Cascade Exchangers, Transporters, Inhibitors. JACS Au 2022, 2, 839–852. [Google Scholar] [CrossRef]
  33. Zilbeyaz, K.; Oztekin, A.; Kutluana, E.G. Design and Synthesis of Garlic-Related Unsymmetrical Thiosulfonates as Potential Alzheimer’s Disease Therapeutics: In Vitro and in Silico Study. Bioorg. Med. Chem. 2021, 40, 116194. [Google Scholar] [CrossRef] [PubMed]
  34. MacDonald, J.A.; Marchand, M.E.; Langler, R.F. Improving upon the in Vitro Biological Activity of Antithrombotic Disulfides. Blood Coagul. Fibrinolysis 2004, 15, 447. [Google Scholar] [CrossRef] [PubMed]
  35. Men’shchikova, E.B.; Zenkov, N.K.; Kozhin, P.M.; Chechushkov, A.V.; Kovner, A.V.; Khrapova, M.V.; Kandalintseva, N.V.; Martinovich, G.G. Synthetic Phenolic Antioxidant TS-13 Suppresses the Growth of Lewis Lung Carcinoma and Potentiates Oncolytic Effect of Doxorubicin. Bull. Exp. Biol. Med. 2019, 166, 646–650. [Google Scholar] [CrossRef]
  36. Smith, M.; Hunter, R.; Stellenboom, N.; Kusza, D.A.; Parker, M.I.; Hammouda, A.N.H.; Jackson, G.; Kaschula, C.H. The Cytotoxicity of Garlic-Related Disulphides and Thiosulfonates in WHCO1 Oesophageal Cancer Cells Is Dependent on S-Thiolation and Not Production of ROS. Biochim. Biophys. Acta BBA—Gen. Subj. 2016, 1860, 1439–1449. [Google Scholar] [CrossRef]
  37. Griffiths, R.; Wong, W.W.-L.; Fletcher, S.P.; Penn, L.Z.; Langler, R.F. Novel Disulfides with Antitumour Efficacy and Specificity. Aust. J. Chem. 2005, 58, 128–136. [Google Scholar] [CrossRef]
  38. Müller, A.; Eller, J.; Albrecht, F.; Prochnow, P.; Kuhlmann, K.; Bandow, J.E.; Slusarenko, A.J.; Leichert, L.I.O. Allicin Induces Thiol Stress in Bacteria through S-Allylmercapto Modification of Protein Cysteines. J. Biol. Chem. 2016, 291, 11477–11490. [Google Scholar] [CrossRef]
  39. Chan, A.N.; Wever, W.J.; Massolo, E.; Allen, S.E.; Li, B. Reducing Holomycin Thiosulfonate to Its Disulfide with Thiols. Chem. Res. Toxicol. 2019, 32, 400–404. [Google Scholar] [CrossRef]
  40. Glendening, E.D.; Reed, A.E.; Carpenter, J.E.; Weinhold, F. NBO, Version 3.1; Gaussian Inc.: Pittsburgh, PA, USA, 2003.
  41. Kupka, T.; Dziuk, B.; Ejsmont, K.; Makieieva, N.; Fizer, L.; Monka, N.; Konechna, R.; Stadnytska, N.; Vasyliuk, S.; Lubenets, V. Impact of Crystal and Molecular Structure of Three Novel Thiosulfonate Crystals on Their Vibrational and NMR Parameters. J. Mol. Struct. 2024, 1313, 138642. [Google Scholar] [CrossRef]
  42. Lubenets, V.; Karpenko, O.; Ponomarenko, M.; Zahoriy, G.; Krychkovska, A.; Novikov, V. Development of New Antimicrobial Compositions of Thiosulfonate Structure. Chem. Chem. Technol. 2013, 7, 119–124. [Google Scholar] [CrossRef]
  43. Frisch, M.J.; Trucks, G.W.; Schlegel, G.E.; Scuseria, M.A.; Robb, J.R.; Cheeseman, G.; Scalmani, V.; Barone, G.A.; Petersson, H.; Nakatsuji, X.; et al. Gaussian 16, Revision C.01; Gaussian, Inc.: Wallingford, CT, USA, 2019.
  44. Barone, V.; Cossi, M.; Tomasi, J. Geometry Optimization of Molecular Structures in Solution by the Polarizable Continuum Model. J. Comput. Chem. 1998, 19, 404–417. [Google Scholar] [CrossRef]
  45. Becke, A.D. Density-Functional Exchange-Energy Approximation with Correct Asymptotic Behavior. Phys. Rev. A 1988, 38, 3098–3100. [Google Scholar] [CrossRef] [PubMed]
  46. Lee, C.; Yang, W.; Parr, R.G. Development of the Colle-Salvetti Correlation-Energy Formula into a Functional of the Electron Density. Phys. Rev. B 1988, 37, 785–789. [Google Scholar] [CrossRef]
  47. Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H. Results Obtained with the Correlation Energy Density Functionals of Becke and Lee, Yang and Parr. Chem. Phys. Lett. 1989, 157, 200–206. [Google Scholar] [CrossRef]
  48. Grimme, S.; Ehrlich, S.; Goerigk, L. Effect of the Damping Function in Dispersion Corrected Density Functional Theory. J. Comput. Chem. 2011, 32, 1456–1465. [Google Scholar] [CrossRef]
  49. Kupka, T.; Stachów, M.; Nieradka, M.; Stobiński, L. DFT Calculation of Structures and NMR Chemical Shifts of Simple Models of Small Diameter Zigzag Single Wall Carbon Nanotubes (SWCNTs). Magn. Reson. Chem. 2011, 49, 549–557. [Google Scholar] [CrossRef] [PubMed]
  50. Chełmecka, E.; Pasterny, K.; Kupka, T.; Stobiński, L. Density Functional Theory Studies of OH-Modified Open-Ended Single-Wall Zigzag Carbon Nanotubes (SWCNTs). J. Mol. Struct. THEOCHEM 2010, 948, 93–98. [Google Scholar] [CrossRef]
  51. Francl, M.M.; Pietro, W.J.; Hehre, W.J.; Binkley, J.S.; Gordon, M.S.; DeFrees, D.J.; Pople, J.A. Self-consistent Molecular Orbital Methods. XXIII. A Polarization-type Basis Set for Second-row Elements. J. Chem. Phys. 1982, 77, 3654–3665. [Google Scholar] [CrossRef]
Molecules 30 02920 g001
Figure 1. Schematic formulas of (A) disulfides, (B) thiosulfinates and (C) thiosulfonates antibiotics [4].
Figure 1. Schematic formulas of (A) disulfides, (B) thiosulfinates and (C) thiosulfonates antibiotics [4].
Molecules 30 02920 g001
Molecules 30 02920 g002
Figure 2. Structures of some organosulfur metabolites of the Allium genus plants with antimicrobial activity.
Figure 2. Structures of some organosulfur metabolites of the Allium genus plants with antimicrobial activity.
Molecules 30 02920 g002
Molecules 30 02920 g003
Figure 3. Structures of thiosulfonates 1−3.
Figure 3. Structures of thiosulfonates 1−3.
Molecules 30 02920 g003
Molecules 30 02920 g004
Figure 4. Antibacterial activity of thiosulfonates 1−3 compared with the control sample against (A) Gram-positive S. aureus and (B) Gram-negative E. coli strains.
Figure 4. Antibacterial activity of thiosulfonates 1−3 compared with the control sample against (A) Gram-positive S. aureus and (B) Gram-negative E. coli strains.
Molecules 30 02920 g004
Molecules 30 02920 g005
Figure 5. Mechanisms of reaction of (A) homolycin and (B) allicin with glutathione or cysteine residues (R3-SH) [38,39].
Figure 5. Mechanisms of reaction of (A) homolycin and (B) allicin with glutathione or cysteine residues (R3-SH) [38,39].
Molecules 30 02920 g005
Molecules 30 02920 g006
Figure 6. Proposed general mechanism of compounds 1−3 antibacterial action.
Figure 6. Proposed general mechanism of compounds 1−3 antibacterial action.
Molecules 30 02920 g006
Table 1. NBO charges and orbitals of -SO2- structural motif in thiosulfonates 1−3, calculated in the gas phase and water (PCM).
Table 1. NBO charges and orbitals of -SO2- structural motif in thiosulfonates 1−3, calculated in the gas phase and water (PCM).
CompoundNBO Charges–Gas PhaseNBO Charges–Water (PCM)
S(O2)O1O2Δ(S-2O)S(O2)O1O2Δ(S-2O)
11.990−0.903−0.8920.1951.914−0.935−0.9390.040
21.986−0.895−0.8930.1981.909−0.927−0.9330.049
32.031−0.898−0.8900.2431.909−0.928−0.9320.049
CompoundNBO Orbitals–Gas Phase, %NBO Orbitals–Water (PCM), %
S(O2)O1S(O2)O2S(O2)O1S(O2)O2
135.9164.0936.2563.7535.7464.2635.9564.05
235.9464.0636.2563.7535.7864.2236.0064.00
336.0064.0036.2563.7535.8164.1936.0163.99
Table 2. NBO charges and orbitals of the -SO- structural motif in thiosulfinates 1−3, calculated in the gas phase and water (PCM).
Table 2. NBO charges and orbitals of the -SO- structural motif in thiosulfinates 1−3, calculated in the gas phase and water (PCM).
CompoundNBO Charges–Gas PhaseNBO Charges–Water (PCM)
S(O)OΔ(S-O)S(O)OΔ(S-O)
11.097−0.9060.1911.100−0.9590.141
21.095−0.9000.1951.109−0.9650.144
31.108−0.8970.2111.103−0.9570.146
CompoundNBO Orbitals–Gas Phase, %NBO Orbitals–Water (PCM), %
S(O)OS(O)O
136.4963.5136.0863.92
236.5463.4636.1463.86
336.5663.4436.1763.83
Table 3. Dissociation energies (kcal/mol) of the S-S bond of 1−3 thiosulfinates without and with ZPE value calculated in vacuum and water (PCM).
Table 3. Dissociation energies (kcal/mol) of the S-S bond of 1−3 thiosulfinates without and with ZPE value calculated in vacuum and water (PCM).
CompoundGas phaseWater (PCM)
EE + ZPEEE + ZPE
1−30.5566−27.8834−31.4194−28.7205
2−34.7697−31.6691−33.9137−31.0096
3−35.1643−32.3023−34.2955−31.4583
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Makieieva, N.; Kupka, T.; Lodowski, P.; Balwierz, R.; Kasperkiewicz, K.; Byrski, A.; Konechna, R.; Lubenets, V. In Search of New Drugs: Elucidating the Activity of Structurally Similar Potential Antibiotics Using Molecular Modelling. Molecules 2025, 30, 2920. https://doi.org/10.3390/molecules30142920

AMA Style

Makieieva N, Kupka T, Lodowski P, Balwierz R, Kasperkiewicz K, Byrski A, Konechna R, Lubenets V. In Search of New Drugs: Elucidating the Activity of Structurally Similar Potential Antibiotics Using Molecular Modelling. Molecules. 2025; 30(14):2920. https://doi.org/10.3390/molecules30142920

Chicago/Turabian Style

Makieieva, Natalina, Teobald Kupka, Piotr Lodowski, Radosław Balwierz, Katarzyna Kasperkiewicz, Adam Byrski, Roksolana Konechna, and Vira Lubenets. 2025. "In Search of New Drugs: Elucidating the Activity of Structurally Similar Potential Antibiotics Using Molecular Modelling" Molecules 30, no. 14: 2920. https://doi.org/10.3390/molecules30142920

APA Style

Makieieva, N., Kupka, T., Lodowski, P., Balwierz, R., Kasperkiewicz, K., Byrski, A., Konechna, R., & Lubenets, V. (2025). In Search of New Drugs: Elucidating the Activity of Structurally Similar Potential Antibiotics Using Molecular Modelling. Molecules, 30(14), 2920. https://doi.org/10.3390/molecules30142920

Article Metrics

Back to TopTop