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16 pages, 5378 KiB

Open AccessEditor’s ChoiceArticle

Alkyl Pyridinol Compounds Exhibit Antimicrobial Effects against Gram-Positive Bacteria

by Juan Canchola, Gracious Yoofi Boafo Donkor, Patrick Ofori Tawiah, Ayoola Fasawe, Emmanuel Ayim, Martin F. Engelke and Jan-Ulrik Dahl

Antibiotics 2024, 13(9), 897; https://doi.org/10.3390/antibiotics13090897 - 20 Sep 2024

Viewed by 1271

Abstract

Background/Objectives. The rise of antibiotic-resistant pathogens represents a significant global challenge in infectious disease control, which is amplified by the decline in the discovery of novel antibiotics. Staphylococcus aureus continues to be a highly significant pathogen, causing infections in multiple organs and tissues [...] Read more.

Background/Objectives. The rise of antibiotic-resistant pathogens represents a significant global challenge in infectious disease control, which is amplified by the decline in the discovery of novel antibiotics. Staphylococcus aureus continues to be a highly significant pathogen, causing infections in multiple organs and tissues in both healthcare institutions and community settings. The bacterium has become increasingly resistant to all available antibiotics. Consequently, there is an urgent need for novel small molecules that inhibit the growth or impair the survival of bacterial pathogens. Given their large structural and chemical diversity, as well as often unique mechanisms of action, natural products represent an excellent avenue for the discovery and development of novel antimicrobial treatments. Anaephene A and B are two such naturally occurring compounds with significant antimicrobial activity against Gram-positive bacteria. Here, we report the rapid syntheses and biological characterization of five novel anaephene derivatives, which display low cytotoxicity against mammalian cells but potent antibacterial activity against various S. aureus strains, including methicillin-resistant S. aureus (MRSA) and the multi-drug-resistant community-acquired strain USA300LAC. Methods. A Sonogashira cross-coupling reaction served as the key step for the synthesis of the alkyl pyridinol products. Results/Conclusions. Using the compound JC-01-074, which displays bactericidal activity already at low concentrations (MIC: 16 μg/mL), we provide evidence that alkyl pyridinols target actively growing and biofilm-forming cells and show that these compounds cause disruption and deformation of the staphylococcal membrane, indicating a membrane-associated mechanism of action. Full article

(This article belongs to the Special Issue Recent Advances in Antimicrobial Drug Discovery, 2nd Edition)

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12 pages, 1929 KiB

Open AccessArticle

Targeting N-Acetylglucosaminidase in Staphylococcus aureus with Iminosugar Inhibitors

by Janja Sluga, Tihomir Tomašič, Marko Anderluh, Martina Hrast Rambaher, Gregor Bajc, Alen Sevšek, Nathaniel I. Martin, Roland J. Pieters, Marjana Novič and Katja Venko

Antibiotics 2024, 13(8), 751; https://doi.org/10.3390/antibiotics13080751 - 10 Aug 2024

Viewed by 1631

Abstract

Bacteria are capable of remarkable adaptations to their environment, including undesirable bacterial resistance to antibacterial agents. One of the most serious cases is an infection caused by multidrug-resistant Staphylococcus aureus, which has unfortunately also spread outside hospitals. Therefore, the development of new [...] Read more.

Bacteria are capable of remarkable adaptations to their environment, including undesirable bacterial resistance to antibacterial agents. One of the most serious cases is an infection caused by multidrug-resistant Staphylococcus aureus, which has unfortunately also spread outside hospitals. Therefore, the development of new effective antibacterial agents is extremely important to solve the increasing problem of bacterial resistance. The bacteriolytic enzyme autolysin E (AtlE) is a promising new drug target as it plays a key role in the degradation of peptidoglycan in the bacterial cell wall. Consequently, disruption of function can have an immense impact on bacterial growth and survival. An in silico and in vitro evaluation of iminosugar derivatives as potent inhibitors of S. aureus (AtlE) was performed. Three promising hit compounds (1, 3 and 8) were identified as AtlE binders in the micromolar range as measured by surface plasmon resonance. The most potent compound among the SPR response curve hits was 1, with a K_D of 19 μM. The K_D value for compound 8 was 88 μM, while compound 3 had a K_D value of 410 μM. Full article

(This article belongs to the Special Issue Recent Advances in Antimicrobial Drug Discovery, 2nd Edition)

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22 pages, 6146 KiB

Open AccessArticle

The Antimicrobial Peptide Capitellacin: Chemical Synthesis of Analogues to Probe the Role of Disulphide Bridges and Their Replacement with Vinyl Sulphides

by Oscar A. Shepperson, Paul W. R. Harris, Margaret A. Brimble and Alan J. Cameron

Antibiotics 2024, 13(7), 615; https://doi.org/10.3390/antibiotics13070615 - 2 Jul 2024

Cited by 1 | Viewed by 1666

Abstract

Capitellacin (1) is a 20-residue antimicrobial β-hairpin, produced by the marine polychaeta (segmented worms) Capitella teletai. Since its discovery in 2020, only very limited studies have been undertaken to understand capitellacin’s structure–activity relationship (SAR). Using fast-flow Fmoc-SPPS, a focused library [...] Read more.

Capitellacin (1) is a 20-residue antimicrobial β-hairpin, produced by the marine polychaeta (segmented worms) Capitella teletai. Since its discovery in 2020, only very limited studies have been undertaken to understand capitellacin’s structure–activity relationship (SAR). Using fast-flow Fmoc-SPPS, a focused library of capitellacin analogues was prepared to systematically study the influence of the two disulphide bridges on its structure and activity, and their replacement with a vinyl sulphide as a potential bioisostere. Upon studying the resulting peptides’ antimicrobial activity and secondary structure, the most terminal disulphide emerged as the most critical element for maintaining both bioactivity and the secondary structure, properties which were demonstrated to be closely interlinked. The removal of the innermost disulphide bridge or disulphide replacement with a vinyl sulphide emerged as strategies with which to tune the activity spectrum, producing selectivity towards E. coli. Additionally, an enantiomeric d-capitellacin analogue revealed mechanistic insights, suggesting that chirality may be an inherent property of capitellacin’s bacterial membrane target, or that a hitherto unknown secondary mechanism of action may exist. Additionally, we propose the Alloc protecting group as a more appropriate alternative to the common Dde group during fast-flow Fmoc-SPPS, in particular for short-chain diamino acids. Full article

(This article belongs to the Special Issue Recent Advances in Antimicrobial Drug Discovery, 2nd Edition)

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16 pages, 4461 KiB

Open AccessArticle

Natural Products Biosynthesis by Streptomyces netropsis IMV Ac-5025 under Exogenous Sterol Action

by Mariia Loboda, Liudmyla Biliavska, Galyna Iutynska, Jake Newitt and Ruslan Mariychuk

Antibiotics 2024, 13(2), 146; https://doi.org/10.3390/antibiotics13020146 - 1 Feb 2024

Cited by 3 | Viewed by 2085

Abstract

Streptomycetes are known as producers of bioactive substances, particularly antibiotics. Streptomyces netropsis IMV Ac-5025 simultaneously produces different classes of antibiotics, including polyene compounds, phytohormones, and sterols, but the metabolic pathways involved in their biosynthesis are largely understudied. The aim of this work was [...] Read more.

Streptomycetes are known as producers of bioactive substances, particularly antibiotics. Streptomyces netropsis IMV Ac-5025 simultaneously produces different classes of antibiotics, including polyene compounds, phytohormones, and sterols, but the metabolic pathways involved in their biosynthesis are largely understudied. The aim of this work was to explore the biosynthesis of polyene antibiotics, sterols, and phytohormones when the producer is cultivated in a nutrient medium supplemented with exogenous β-sitosterol. Gas chromatography and high-performance liquid chromatography were applied to analyze the spectrum of bioactive compounds. The obtained results demonstrated not only an increase in the accumulation of biomass but also polyene antibiotics, intracellular sterols, auxins, and cytokinins, when cultivating S. netropsis IMV Ac-5025 in a liquid medium with the addition of β-sitosterol. The amount of biomass raised 1.5–2-fold, whilst the sum of polyene antibiotics increased 4.5-fold, sterols’ sum (ergosterol, cholesterol, stigmasterol, β-sitosterol, and 24-epibrassinolide) by 2.9-fold, auxins’ sum (indole-3-acetic acid, indole-3-acetic acid hydrazide, indole-3-carbinol, indole-3-butyric acid, indole-3-carboxaldehyde, and indole-3-carboxylic acid) by 6-fold, and cytokinins’ sum (zeatin, isopentyladenine, zeatin riboside, and isopentenyladenosine) by 11-fold. Thus, we put forward the hypothesis that β-sitosterol plays a regulatory role in the network of biosynthetic reactions of S. netropsis IMV Ac-5025. Full article

(This article belongs to the Special Issue Recent Advances in Antimicrobial Drug Discovery, 2nd Edition)

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22 pages, 1837 KiB

Open AccessArticle

GATR-3, a Peptide That Eradicates Preformed Biofilms of Multidrug-Resistant Acinetobacter baumannii

by Monique L. van Hoek, Fahad M. Alsaab and Ashley M. Carpenter

Antibiotics 2024, 13(1), 39; https://doi.org/10.3390/antibiotics13010039 - 31 Dec 2023

Cited by 2 | Viewed by 2936

Abstract

Acinetobacter baumannii is a gram-negative bacterium that causes hospital-acquired and opportunistic infections, resulting in pneumonia, sepsis, and severe wound infections that can be difficult to treat due to antimicrobial resistance and the formation of biofilms. There is an urgent need to develop novel [...] Read more.

Acinetobacter baumannii is a gram-negative bacterium that causes hospital-acquired and opportunistic infections, resulting in pneumonia, sepsis, and severe wound infections that can be difficult to treat due to antimicrobial resistance and the formation of biofilms. There is an urgent need to develop novel antimicrobials to tackle the rapid increase in antimicrobial resistance, and antimicrobial peptides (AMPs) represent an additional class of potential agents with direct antimicrobial and/or host-defense activating activities. In this study, we present GATR-3, a synthetic, designed AMP that was modified from a cryptic peptide discovered in American alligator, as our lead peptide to target multidrug-resistant (MDR) A. baumannii. Antimicrobial susceptibility testing and antibiofilm assays were performed to assess GATR-3 against a panel of 8 MDR A. baumannii strains, including AB5075 and some clinical strains. The GATR-3 mechanism of action was determined to be via loss of membrane integrity as measured by DiSC₃(5) and ethidium bromide assays. GATR-3 exhibited potent antimicrobial activity against all tested multidrug-resistant A. baumannii strains with rapid killing. Biofilms are difficult to treat and eradicate. Excitingly, GATR-3 inhibited biofilm formation and, more importantly, eradicated preformed biofilms of MDR A. baumannii AB5075, as evidenced by MBEC assays and scanning electron micrographs. GATR3 did not induce resistance in MDR A. baumannii, unlike colistin. Additionally, the toxicity of GATR-3 was evaluated using human red blood cells, HepG2 cells, and waxworms using hemolysis and MTT assays. GATR-3 demonstrated little to no cytotoxicity against HepG2 and red blood cells, even at 100 μg/mL. GATR-3 injection showed little toxicity in the waxworm model, resulting in a 90% survival rate. The therapeutic index of GATR-3 was estimated (based on the HC₅₀/MIC against human RBCs) to be 1250. Overall, GATR-3 is a promising candidate to advance to preclinical testing to potentially treat MDR A. baumannii infections. Full article

(This article belongs to the Special Issue Recent Advances in Antimicrobial Drug Discovery, 2nd Edition)

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15 pages, 2157 KiB

Open AccessArticle

Preclinical Evaluation of Nitroxide-Functionalised Ciprofloxacin as a Novel Antibiofilm Drug Hybrid for Urinary Tract Infections

by Sophia Hawas, Jilong Qin, Sandra Wiedbrauk, Kathryn Fairfull-Smith and Makrina Totsika

Antibiotics 2023, 12(10), 1479; https://doi.org/10.3390/antibiotics12101479 - 22 Sep 2023

Viewed by 1715

Abstract

Urinary tract infections (UTIs) are the second most common bacterial infection with high recurrence rates and can involve biofilm formation on patient catheters. Biofilms are inherently tolerant to antimicrobials, making them difficult to eradicate. Many antibiofilm agents alone do not have bactericidal activity; [...] Read more.

Urinary tract infections (UTIs) are the second most common bacterial infection with high recurrence rates and can involve biofilm formation on patient catheters. Biofilms are inherently tolerant to antimicrobials, making them difficult to eradicate. Many antibiofilm agents alone do not have bactericidal activity; therefore, linking them to antibiotics is a promising antibiofilm strategy. However, many of these hybrid agents have not been tested in relevant preclinical settings, limiting their potential for clinical translation. Here, we evaluate a ciprofloxacin di-nitroxide hybrid (CDN11), previously reported to have antibiofilm activity against uropathogenic Escherichia coli (UPEC) strain UTI89 in vitro, as a potential UTI therapeutic using multiple preclinical models that reflect various aspects of UTI pathogenesis. We report improved in vitro activity over the parent drug ciprofloxacin against mature UTI89 biofilms formed inside polyethylene catheters. In bladder cell monolayers infected with UTI89, treatment with CDN11 afforded significant reduction in bacterial titers, including intracellular UPEC. Infected mouse bladders containing biofilm-like intracellular reservoirs of UPEC UTI89 showed decreased bacterial loads after ex vivo bladder treatment with CDN11. Activity for CDN11 was reported across different models of UTI, showcasing nitroxide–antibiotic hybridization as a promising antibiofilm approach. The pipeline we described here could be readily used in testing other new therapeutic compounds, fast-tracking the development of novel antibiofilm therapeutics. Full article

(This article belongs to the Special Issue Recent Advances in Antimicrobial Drug Discovery, 2nd Edition)

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Review

Jump to: Research

10 pages, 2253 KiB

Open AccessReview

Meropenem/Vaborbactam—A Mechanistic Review for Insight into Future Development of Combinational Therapies

by Trae Hillyer and Woo Shik Shin

Antibiotics 2024, 13(6), 472; https://doi.org/10.3390/antibiotics13060472 - 21 May 2024

Cited by 2 | Viewed by 1968

Abstract

Beta-lactam antibiotics have been a major climacteric in medicine for being the first bactericidal compound available for clinical use. They have continually been prescribed since their development in the 1940s, and their application has saved an immeasurable number of lives. With such immense [...] Read more.

Beta-lactam antibiotics have been a major climacteric in medicine for being the first bactericidal compound available for clinical use. They have continually been prescribed since their development in the 1940s, and their application has saved an immeasurable number of lives. With such immense use, the rise in antibiotic resistance has truncated the clinical efficacy of these compounds. Nevertheless, the synergism of combinational antibiotic therapy has allowed these drugs to burgeon once again. Here, the development of meropenem with vaborbactam—a recently FDA-approved beta-lactam combinational therapy—is reviewed in terms of structure rationale, activity gamut, pharmacodynamic/pharmacokinetic properties, and toxicity to provide insight into the future development of analogous therapies. Full article

(This article belongs to the Special Issue Recent Advances in Antimicrobial Drug Discovery, 2nd Edition)

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28 pages, 1373 KiB

Open AccessReview

Antimicrobial Properties of Colostrum and Milk

by Furkan Eker, Emir Akdaşçi, Hatice Duman, Yalçın Mert Yalçıntaş, Ahmet Alperen Canbolat, Arda Erkan Kalkan, Sercan Karav and Dunja Šamec

Antibiotics 2024, 13(3), 251; https://doi.org/10.3390/antibiotics13030251 - 11 Mar 2024

Cited by 25 | Viewed by 6164

Abstract

The growing number of antibiotic resistance genes is putting a strain on the ecosystem and harming human health. In addition, consumers have developed a cautious attitude towards chemical preservatives. Colostrum and milk are excellent sources of antibacterial components that help to strengthen the [...] Read more.

The growing number of antibiotic resistance genes is putting a strain on the ecosystem and harming human health. In addition, consumers have developed a cautious attitude towards chemical preservatives. Colostrum and milk are excellent sources of antibacterial components that help to strengthen the immunity of the offspring and accelerate the maturation of the immune system. It is possible to study these important defenses of milk and colostrum, such as lactoferrin, lysozyme, immunoglobulins, oligosaccharides, etc., as biotherapeutic agents for the prevention and treatment of numerous infections caused by microbes. Each of these components has different mechanisms and interactions in various places. The compound’s mechanisms of action determine where the antibacterial activity appears. The activation of the antibacterial activity of milk and colostrum compounds can start in the infant’s mouth during lactation and continue in the gastrointestinal regions. These antibacterial properties possess potential for therapeutic uses. In order to discover new perspectives and methods for the treatment of bacterial infections, additional investigations of the mechanisms of action and potential complexes are required. Full article

(This article belongs to the Special Issue Recent Advances in Antimicrobial Drug Discovery, 2nd Edition)

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