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Antibacterial Agents 2021

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

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 24895

Special Issue Editor


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Guest Editor
Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, 881 Madison Avenue, Memphis, TN 38163, USA
Interests: anti-cancer drugs; antibiotics; antibacterial agents; bacterial infections; drug-resistant pathogens; medicinal chemistry; natural products; rational drug design; repurposing existing drugs and drug targets
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Special Issue Information

Dear Colleagues,

Multidrug-resistant (MDR) bacteria are one of the highest threats to health worldwide. The most important drugs currently in clinical use were introduced in the period between the 1950s and 1980s. A lack of established treatment guidelines for MDR bacterial infections and misuse of drugs that cause mutations in bacterial genomes have led to an increase in antibiotic resistance. Some Gram-negative bacteria have already acquired pandrug resistance. Drug-resistant spore-forming Bacillus spp. are difficult to treat with current medications. Drug-resistant Mycobacterium spp. remains one of the most difficult pathogens to cure without long treatment regimens.

Although such antibiotic resistances are an increasing threat, the development of new antimicrobial agents is declining due in large part to the fact that research and development in large pharmaceutical industries have been toward drug development of the leading chronic diseases in the last few decades. Continuous development of antibacterial agents and treatment methods is important to reduce the global threat of antibiotic resistance. Over the last few decades, antibacterial drug discovery has advanced to unique translational sciences, including target-oriented drug discovery, structural biochemistry of transmembrane proteins, new synthetic schemes, drug delivery approaches, and high-throughput assay methods.

The aim of this Special Issue is to cover recent advances in the discovery of antibacterial agents. This Special Issue may include original research articles and reviews on drug targets, medicinal chemistry, new chemical entities, structural biochemistry of unexploited targets, phage therapy, vaccine, new formulations, drug delivery, pharmacokinetics and dynamic aspects, and new strategies to use approved drugs.

Prof. Dr. Michio Kurosu
Guest Editor

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Keywords

  • antibacterial agents
  • medicinal chemistry
  • antibacterial drug discovery
  • antibacterial pharmacology
  • rational drug design of antibacterial agents
  • antibacterial drug delivery
  • structural biochemistry

Published Papers (8 papers)

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Research

20 pages, 9312 KiB  
Article
Amino Alcohols as Potential Antibiotic and Antifungal Leads
by Jennifer R. Baker, Peter J. Cossar, Mark A. T. Blaskovich, Alysha G. Elliott, Johannes Zuegg, Matthew A. Cooper, Peter J. Lewis and Adam McCluskey
Molecules 2022, 27(7), 2050; https://doi.org/10.3390/molecules27072050 - 22 Mar 2022
Cited by 3 | Viewed by 3502
Abstract
Five focused compound libraries (forty-nine compounds), based on prior studies in our laboratory were synthesized and screened for antibiotic and anti-fungal activity against S. aureus, E. coli, K. pneumoniae, P. aeruginosa, A. baumannii, C. albicans [...] Read more.
Five focused compound libraries (forty-nine compounds), based on prior studies in our laboratory were synthesized and screened for antibiotic and anti-fungal activity against S. aureus, E. coli, K. pneumoniae, P. aeruginosa, A. baumannii, C. albicans and C. neoformans. Low levels of activity, at the initial screening concentration of 32 μg/mL, were noted with analogues of (Z)-2-(3,4-dichlorophenyl)-3-phenylacrylonitriles which made up the first two focused libraries produced. The most promising analogues possessing additional substituents on the terminal aromatic ring of the synthesised acrylonitriles. Modifications of the terminal aromatic moiety were explored through epoxide installation flowed by flow chemistry mediated ring opening aminolysis with discreet sets of amines to the corresponding amino alcohols. Three new focused libraries were developed from substituted anilines, cyclic amines, and phenyl linked heterocyclic amines. The aniline-based compounds were inactive against the bacterial and fungal lines screened. The introduction of a cyclic, such as piperidine, piperazine, or morpholine, showed >50% inhibition when evaluated at 32 μg/mL compound concentration against methicillin-resistant Staphylococcus aureus. Examination of the terminal aromatic substituent via oxirane aminolysis allowed for the synthesis of three new focused libraries of afforded amino alcohols. Aromatic substituted piperidine or piperazine switched library activity from antibacterial to anti-fungal activity with ((Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)phenyl)acrylonitrile), ((Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(4-(4-hydroxyphenyl)piperazin-1-yl)propoxy)-phenyl)acrylonitrile) and ((Z)-3-(4-(3-(4-cyclohexylpiperazin-1-yl)-2-hydroxypropoxy)-phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile) showing >95% inhibition of Cryptococcus neoformans var. grubii H99 growth at 32 μg/mL. While (Z)-3-(4-(3-(cyclohexylamino)-2-hydroxypropoxy)phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile, (S,Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)acrylonitrile, (R,Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)acrylonitrile, (Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(D-11-piperidin-1-yl)propoxy)phenyl)-acrylonitrile, and (Z)-3-(4-(3-(4-cyclohexylpiperazin-1-yl)-2-hydroxypropoxy)-phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile 32 μg/mL against Staphylococcus aureus. Full article
(This article belongs to the Special Issue Antibacterial Agents 2021)
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16 pages, 3224 KiB  
Article
Glycosides of Nadifloxacin—Synthesis and Antibacterial Activities against Methicillin-Resistant Staphylococcus aureus
by Mark Hutchins, Richard A. Bovill, Peter J. Stephens, John A. Brazier and Helen M. I. Osborn
Molecules 2022, 27(5), 1504; https://doi.org/10.3390/molecules27051504 - 23 Feb 2022
Cited by 1 | Viewed by 1693
Abstract
The increase in the number of bacteria that are resistant to multiple antibiotics poses a serious clinical problem that threatens the health of humans worldwide. Nadifloxacin (1) is a highly potent antibacterial agent with broad-spectrum activity. However, its poor aqueous solubility [...] Read more.
The increase in the number of bacteria that are resistant to multiple antibiotics poses a serious clinical problem that threatens the health of humans worldwide. Nadifloxacin (1) is a highly potent antibacterial agent with broad-spectrum activity. However, its poor aqueous solubility has limited its use to topical applications. To increase its solubility, it was glycosylated herein to form a range of trans-linked (3a-e) and cis-linked (7a,b) glycosides, each of which was prepared and purified to afford single anomers. The seven glycoside derivatives (3a-e, 7a,b) were examined for potency against eight strains of S. aureus, four of which were methicillin-resistant. Although less potent than free nadifloxacin (1), the α-L-arabinofuransoside (3a) was effective against all strains that were tested (minimum inhibitory concentrations of 1–8 μg/mL compared to 0.1–0.25 μg/mL for nadifloxacin), demonstrating the potential of this glycoside as an antibacterial agent. Estimation of Log P as well as observations made during preparation of these compounds reveal that the solubilities of the glycosides were greatly improved compared with nadifloxacin (1), raising the prospect of its use in oral applications. Full article
(This article belongs to the Special Issue Antibacterial Agents 2021)
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27 pages, 10859 KiB  
Article
Synthesis, Biological Evaluation and Molecular Docking Studies of 5-Indolylmethylen-4-oxo-2-thioxothiazolidine Derivatives
by Volodymyr Horishny, Athina Geronikaki, Victor Kartsev, Vasyl Matiychuk, Anthi Petrou, Pavel Pogodin, Vladimir Poroikov, Theodora A. Papadopoulou, Ioannis S. Vizirianakis, Marina Kostic, Marija Ivanov and Marina Sokovic
Molecules 2022, 27(3), 1068; https://doi.org/10.3390/molecules27031068 - 5 Feb 2022
Cited by 7 | Viewed by 2849
Abstract
Background: Infectious diseases represent a significant global strain on public health security and impact on socio-economic stability all over the world. The increasing resistance to the current antimicrobial treatment has resulted in the crucial need for the discovery and development of novel entities [...] Read more.
Background: Infectious diseases represent a significant global strain on public health security and impact on socio-economic stability all over the world. The increasing resistance to the current antimicrobial treatment has resulted in the crucial need for the discovery and development of novel entities for the infectious treatment with different modes of action that could target both sensitive and resistant strains. Methods: Compounds were synthesized using the classical organic chemistry methods. Prediction of biological activity spectra was carried out using PASS and PASS-based web applications. Pharmacophore modeling in LigandScout software was used for quantitative modeling of the antibacterial activity. Antimicrobial activity was evaluated using the microdilution method. AutoDock 4.2® software was used to elucidate probable bacterial and fungal molecular targets of the studied compounds. Results: All compounds exhibited better antibacterial potency than ampicillin against all bacteria tested. Three compounds were tested against resistant strains MRSA, P. aeruginosa and E. coli and were found to be more potent than MRSA than reference drugs. All compounds demonstrated a higher degree of antifungal activity than the reference drugs bifonazole (6–17-fold) and ketoconazole (13–52-fold). Three of the most active compounds could be considered for further development of the new, more potent antimicrobial agents. Conclusion: Compounds 5b (Z)-3-(3-hydroxyphenyl)-5-((1-methyl-1H-indol-3-yl)methylene)-2-thioxothiazolidin-4-one and 5g (Z)-3-[5-(1H-Indol-3-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-benzoic acid as well as 5h (Z)-3-(5-((5-methoxy-1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)benzoic acid can be considered as lead compounds for further development of more potent and safe antibacterial and antifungal agents. Full article
(This article belongs to the Special Issue Antibacterial Agents 2021)
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22 pages, 7114 KiB  
Article
Discovery of Novel Pleuromutilin Derivatives as Potent Antibacterial Agents for the Treatment of MRSA Infection
by Han-Qing Fang, Jie Zeng, Shou-Kai Wang, Xiao Wang, Fang Chen, Bo Li, Jie Liu, Zhen Jin, Ya-Hong Liu and You-Zhi Tang
Molecules 2022, 27(3), 931; https://doi.org/10.3390/molecules27030931 - 29 Jan 2022
Cited by 6 | Viewed by 2192
Abstract
A series of novel pleuromutilin derivatives containing nitrogen groups on the side chain of C14 were synthesized under mild conditions. Most of the synthesized derivatives displayed potent antibacterial activities. Compound 9 was found to be the most active antibacterial derivative against MRSA (MIC [...] Read more.
A series of novel pleuromutilin derivatives containing nitrogen groups on the side chain of C14 were synthesized under mild conditions. Most of the synthesized derivatives displayed potent antibacterial activities. Compound 9 was found to be the most active antibacterial derivative against MRSA (MIC = 0.06 μg/mL). Furthermore, the result of time-kill curves showed that compound 9 had a certain inhibitory effect against MRSA in vitro. Moreover, according to a surface plasmon resonance (SPR) study, compound 9 (KD = 1.77 × 10−8 M) showed stronger affinity to the 50S ribosome than tiamulin (KD = 2.50 × 10−8 M). The antibacterial activity of compound 9 was further evaluated in an MRSA-infected murine thigh model. Compared to the negative control group, tiamulin reduced MRSA load (~0.7 log10 CFU/mL), and compound 9 performed a treatment effect (~1.3 log10 CFU/mL). In addition, compound 9 was evaluated in CYP450 inhibition assay and showed only moderate in vitro CYP3A4 inhibition (IC50 = 2.92 μg/mL). Full article
(This article belongs to the Special Issue Antibacterial Agents 2021)
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20 pages, 2366 KiB  
Article
Quantitative Determination of Unbound Piperacillin and Imipenem in Biological Material from Critically Ill Using Thin-Film Microextraction-Liquid Chromatography-Mass Spectrometry
by Robert Włodarski, Karolina Żuchowska and Wojciech Filipiak
Molecules 2022, 27(3), 926; https://doi.org/10.3390/molecules27030926 - 29 Jan 2022
Cited by 6 | Viewed by 2574
Abstract
β-Lactam antibiotics are most commonly used in the critically ill, but their effective dosing is challenging and may result in sub-therapeutic concentrations that can lead to therapy failure and even promote antimicrobial resistance. In this study, we present the analytical tool enabling specific [...] Read more.
β-Lactam antibiotics are most commonly used in the critically ill, but their effective dosing is challenging and may result in sub-therapeutic concentrations that can lead to therapy failure and even promote antimicrobial resistance. In this study, we present the analytical tool enabling specific and sensitive determination of the sole biologically active fraction of piperacillin and imipenem in biological material from the critically ill. Thin-film microextraction sampling technique, followed by rapid liquid chromatography–tandem mass spectrometry (LC-MS/MS) analysis, was optimized and validated for the quantitative determination of antibiotics in blood and bronchoalveolar lavage (BAL) specimens collected from intensive care unit (ICU) patients suffering from ventilation-associated pneumonia (n = 18 and n = 9, respectively). The method was optimized and proved to meet the criteria of US Food and Drug Administration (FDA) guidelines for bioanalytical method validation. Highly selective, sensitive, accurate and precise analysis by means of thin-film microextraction–LC-MS/MS, which is not affected by matrix-related factors, was successfully applied in clinical settings, revealing poor penetration of piperacillin and imipenem from blood into BAL fluid (reflecting the site of bacterial infection), nonlinearity in antibiotic binding to plasma-proteins and drug-specific dependence on creatinine clearance. This work demonstrates that only a small fraction of biologically active antibiotics reach the site of infection, providing clinicians with a high-throughput analytical tool for future studies on personalized therapeutic drug monitoring when tailoring the dosing strategy to an individual patient. Full article
(This article belongs to the Special Issue Antibacterial Agents 2021)
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21 pages, 2701 KiB  
Article
Antibacterial Activity of Pharmaceutical-Grade Rose Bengal: An Application of a Synthetic Dye in Antibacterial Therapies
by Michio Kurosu, Katsuhiko Mitachi, Junshu Yang, Edward V. Pershing, Bruce D. Horowitz, Eric A. Wachter, John W. Lacey III, Yinduo Ji and Dominic J. Rodrigues
Molecules 2022, 27(1), 322; https://doi.org/10.3390/molecules27010322 (registering DOI) - 5 Jan 2022
Cited by 17 | Viewed by 5300
Abstract
Rose bengal has been used in the diagnosis of ophthalmic disorders and liver function, and has been studied for the treatment of solid tumor cancers. To date, the antibacterial activity of rose bengal has been sporadically reported; however, these data have been generated [...] Read more.
Rose bengal has been used in the diagnosis of ophthalmic disorders and liver function, and has been studied for the treatment of solid tumor cancers. To date, the antibacterial activity of rose bengal has been sporadically reported; however, these data have been generated with a commercial grade of rose bengal, which contains major uncontrolled impurities generated by the manufacturing process (80–95% dye content). A high-purity form of rose bengal formulation (HP-RBf, >99.5% dye content) kills a battery of Gram-positive bacteria, including drug-resistant strains at low concentrations (0.01–3.13 μg/mL) under fluorescent, LED, and natural light in a few minutes. Significantly, HP-RBf effectively eradicates Gram-positive bacterial biofilms. The frequency that Gram-positive bacteria spontaneously developed resistance to HP-RB is extremely low (less than 1 × 10−13). Toxicity data obtained through our research programs indicate that HP-RB is feasible as an anti-infective drug for the treatment of skin and soft tissue infections (SSTIs) involving multidrug-resistant (MDR) microbial invasion of the skin, and for eradicating biofilms. This article summarizes the antibacterial activity of pharmaceutical-grade rose bengal, HP-RB, against Gram-positive bacteria, its cytotoxicity against skin cells under illumination conditions, and mechanistic insights into rose bengal’s bactericidal activity under dark conditions. Full article
(This article belongs to the Special Issue Antibacterial Agents 2021)
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8 pages, 1315 KiB  
Article
Assignment of Absolute Configurations of Two Promising Anti-Helicobacter pylori Agents from the Marine Sponge-Derived Fungus Aspergillus niger L14
by Jia Liu, Ronglu Yu, Jia Jia, Wen Gu and Huawei Zhang
Molecules 2021, 26(16), 5061; https://doi.org/10.3390/molecules26165061 - 20 Aug 2021
Cited by 4 | Viewed by 2049
Abstract
A chemical investigation into endozoic fungus Aspergillus niger L14 derived from the marine sponge of Reniera japonica collected off Xinghai Bay (China) resulted in the isolation of two dimeric naphtho-γ-pyrones, fonsecinone A (1) and isoaurasperone A (2). [...] Read more.
A chemical investigation into endozoic fungus Aspergillus niger L14 derived from the marine sponge of Reniera japonica collected off Xinghai Bay (China) resulted in the isolation of two dimeric naphtho-γ-pyrones, fonsecinone A (1) and isoaurasperone A (2). Through a combination of ECD spectra and X-ray diffraction analysis, the chiral axes of compounds 1 and 2 were unambiguously determined as Rα-configurations. Bioassay results indicated that these substances exhibited remarkably inhibitory effects on human pathogens Helicobacter pylori G27 and 159 with MIC values of ≤4 μg/mL, which are similar to those of the positive control, ampicillin sodium. To the best of our knowledge, this is the first report on absolute configuration of 1 and crystallographic data of 2, as well as their potent anti-H. pylori activities. Full article
(This article belongs to the Special Issue Antibacterial Agents 2021)
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21 pages, 3582 KiB  
Article
Chromenol Derivatives as Novel Antifungal Agents: Synthesis, In Silico and In Vitro Evaluation
by Marina Zveaghintseva, Eugenia Stingaci, Serghei Pogrebnoi, Anastasia Smetanscaia, Vladimir Valica, Livia Uncu, Victor Ch. Kravtsov, Elena Melnic, Anthi Petrou, Jasmina Glamočlija, Marina Soković, Alejandro Carazo, Přemysl Mladěnka, Vladimir Poroikov, Athina Geronikaki and Fliur Z. Macaev
Molecules 2021, 26(14), 4304; https://doi.org/10.3390/molecules26144304 - 16 Jul 2021
Cited by 11 | Viewed by 3213
Abstract
Herein we report the synthesis of some new 1H-1,2,4-triazole functionalized chromenols (3a3n) via tandem reactions of 1-(alkyl/aryl)-2-(1H-1,2,4-triazole-1-yl) with salicylic aldehydes and the evaluation of their antifungal activity. In silico prediction of biological activity with computer [...] Read more.
Herein we report the synthesis of some new 1H-1,2,4-triazole functionalized chromenols (3a3n) via tandem reactions of 1-(alkyl/aryl)-2-(1H-1,2,4-triazole-1-yl) with salicylic aldehydes and the evaluation of their antifungal activity. In silico prediction of biological activity with computer program PASS indicate that the compounds have a high novelty compared to the known antifungal agents. We did not find any close analog among the over 580,000 pharmaceutical agents in the Cortellis Drug Discovery Intelligence database at the similarity cutoff of 70%. The evaluation of antifungal activity in vitro revealed that the highest activity was exhibited by compound 3k, followed by 3n. Their MIC values for different fungi were 22.1–184.2 and 71.3–199.8 µM, respectively. Twelve from fourteen tested compounds were more active than the reference drugs ketoconazole and bifonazole. The most sensitive fungus appeared to be Trichoderma viride, while Aspergillus fumigatus was the most resistant one. It was found that the presence of the 2-(tert-butyl)-2H-chromen-2-ol substituent on the 4th position of the triazole ring is very beneficial for antifungal activity. Molecular docking studies on C. albicans sterol 14α-demethylase (CYP51) and DNA topoisomerase IV were used to predict the mechanism of antifungal activities. According to the docking results, the inhibition of CYP51 is a putative mechanism of antifungal activity of the novel chromenol derivatives. We also showed that most active compounds have a low cytotoxicity, which allows us to consider them promising antifungal agents for the subsequent testing activity in in vivo assays. Full article
(This article belongs to the Special Issue Antibacterial Agents 2021)
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