Editorial

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Open AccessEditorial

Bacterial and Fungal Pathogens: New Weapons to Fight Them

by Charlotte A. Huber

Antibiotics 2024, 13(5), 384; https://doi.org/10.3390/antibiotics13050384 - 24 Apr 2024

Viewed by 190

Abstract

In high-income countries, degenerative diseases are the primary cause of death [...] Full article

(This article belongs to the Special Issue Molecular Methods in Antibiotics Discovery)

Research

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21 pages, 2897 KiB

Open AccessEditor’s ChoiceArticle

Size-Controlled Ammonium-Based Homopolymers as Broad-Spectrum Antibacterials

by Meltem Haktaniyan, Richa Sharma and Mark Bradley

Antibiotics 2023, 12(8), 1320; https://doi.org/10.3390/antibiotics12081320 - 16 Aug 2023

Viewed by 1234

Abstract

Ammonium group containing polymers possess inherent antimicrobial properties, effectively eliminating or preventing infections caused by harmful microorganisms. Here, homopolymers based on monomers containing ammonium groups were synthesized via Reversible Addition Fragmentation Chain Transfer Polymerization (RAFT) and evaluated as potential antibacterial agents. The antimicrobial [...] Read more.

Ammonium group containing polymers possess inherent antimicrobial properties, effectively eliminating or preventing infections caused by harmful microorganisms. Here, homopolymers based on monomers containing ammonium groups were synthesized via Reversible Addition Fragmentation Chain Transfer Polymerization (RAFT) and evaluated as potential antibacterial agents. The antimicrobial activity was evaluated against Gram-positive (M. luteus and B. subtilis) and Gram-negative bacteria (E. coli and S. typhimurium). Three polymers, poly(diallyl dimethyl ammonium chloride), poly([2-(methacryloyloxy)ethyl]trimethylammonium chloride), and poly(vinyl benzyl trimethylammonium chloride), were examined to explore the effect of molecular weight (10 kDa, 20 kDa, and 40 kDa) on their antimicrobial activity and toxicity to mammalian cells. The mechanisms of action of the polymers were investigated with dye-based assays, while Scanning Electron Microscopy (SEM) showed collapsed and fused bacterial morphologies due to the interactions between the polymers and components of the bacterial cell envelope, with some polymers proving to be bactericidal and others bacteriostatic, while being non-hemolytic. Among all the homopolymers, the most active, non-Gram-specific polymer was poly([2-(methacryloyloxy)ethyl]trimethylammonium chloride), with a molecular weight of 40 kDa, with minimum inhibitory concentrations between 16 and 64 µg/mL, showing a bactericidal mode of action mediated by disruption of the cytoplasmic membrane. This homopolymer could be useful in biomedical applications such as surface dressings and in areas such as eye infections. Full article

(This article belongs to the Special Issue Molecular Methods in Antibiotics Discovery)

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26 pages, 20249 KiB

Open AccessArticle

Design, Synthesis, and Structure–Activity Relationship Studies of New Quinone Derivatives as Antibacterial Agents

by Juan Andrades-Lagos, Javier Campanini-Salinas, América Pedreros-Riquelme, Jaime Mella, Duane Choquesillo-Lazarte, P. P. Zamora, Hernán Pessoa-Mahana, Ian Burbulis and David Vásquez-Velásquez

Antibiotics 2023, 12(6), 1065; https://doi.org/10.3390/antibiotics12061065 - 16 Jun 2023

Cited by 1 | Viewed by 2143

Abstract

Resistance to antibacterial agents is a growing global public health problem that reduces the efficacy of available antibacterial agents, leading to increased patient mortality and morbidity. Unfortunately, only 16 antibacterial drugs have been approved by the FDA in the last 10 years, so [...] Read more.

Resistance to antibacterial agents is a growing global public health problem that reduces the efficacy of available antibacterial agents, leading to increased patient mortality and morbidity. Unfortunately, only 16 antibacterial drugs have been approved by the FDA in the last 10 years, so it is necessary to develop new agents with novel chemical structures and/or mechanisms of action. In response to this, our group takes up the challenge of designing a new family of pyrimidoisoquinolinquinones displaying antimicrobial activities against multidrug-resistant Gram-positive bacteria. Accordingly, the objective of this study was to establish the necessary structural requirements to obtain compounds with high antibacterial activity, along with the parameters controlling antibacterial activity. To achieve this goal, we designed a family of compounds using different strategies for drug design. Forty structural candidates were synthesized and characterized, and antibacterial assays were carried out against high-priority bacterial pathogens. A variety of structural properties were modified, such as hydrophobicity and chain length of functional groups attached to specific carbon positions of the quinone core. All the synthesized compounds inhibited Gram-positive pathogens in concentrations ranging from 0.5 to 64 µg/mL. Two derivatives exhibited minimum inhibitory concentrations of 64 µg/mL against Klebsiella pneumoniae, while compound 28 demonstrated higher potency against MRSA than vancomycin. Full article

(This article belongs to the Special Issue Molecular Methods in Antibiotics Discovery)

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22 pages, 9467 KiB

Open AccessArticle

Exploring the Antimicrobial Activity of Sodium Titanate Nanotube Biomaterials in Combating Bone Infections: An In Vitro and In Vivo Study

by Atiah H. Almalki, Walid Hamdy Hassan, Amany Belal, Ahmed Farghali, Romissaa M. Saleh, Abeer Enaiet Allah, Abdalla Abdelwahab, Sangmin Lee, Ahmed H.E. Hassan, Mohammed M. Ghoneim, Omeima Abdullah, Rehab Mahmoud and Fatma I. Abo El-Ela

Antibiotics 2023, 12(5), 799; https://doi.org/10.3390/antibiotics12050799 - 22 Apr 2023

Cited by 2 | Viewed by 1980

Abstract

The majority of bone and joint infections are caused by Gram-positive organisms, specifically staphylococci. Additionally, gram-negative organisms such as E. coli can infect various organs through infected wounds. Fungal arthritis is a rare condition, with examples including Mucormycosis (Mucor rhizopus). These [...] Read more.

The majority of bone and joint infections are caused by Gram-positive organisms, specifically staphylococci. Additionally, gram-negative organisms such as E. coli can infect various organs through infected wounds. Fungal arthritis is a rare condition, with examples including Mucormycosis (Mucor rhizopus). These infections are difficult to treat, making the use of novel antibacterial materials for bone diseases crucial. Sodium titanate nanotubes (NaTNTs) were synthesized using the hydrothermal method and characterized using a Field Emission Scanning Electron Microscope (FESEM), High-Resolution Transmission Electron Microscope (HRTEM), X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), Brunauer–Emmett–Teller (BET), and Zeta sizer. The antibacterial and antifungal activity of the NaTNT framework nanostructure was evaluated using Minimum Inhibitory Concentration (MIC), Minimum Bactericidal Concentration (MBC), Disc Diffusion assays for bacterial activity, and Minimum Fungicidal Concentration (MFC) for antifungal investigation. In addition to examining in vivo antibacterial activity in rats through wound induction and infection, pathogen counts and histological examinations were also conducted. In vitro and in vivo tests revealed that NaTNT has substantial antifungal and antibacterial effects on various bone-infected pathogens. In conclusion, current research indicates that NaTNT is an efficient antibacterial agent against a variety of microbial pathogenic bone diseases. Full article

(This article belongs to the Special Issue Molecular Methods in Antibiotics Discovery)

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14 pages, 942 KiB

Open AccessArticle

Synthesis, Characterization, Cytotoxicity Analysis and Evaluation of Novel Heterocyclic Derivatives of Benzamidine against Periodontal Disease Triggering Bacteria

by Ramasamy Kavitha, Mohammad Auwal Sa’ad, Shivkanya Fuloria, Neeraj Kumar Fuloria, Manickam Ravichandran and Pattabhiraman Lalitha

Antibiotics 2023, 12(2), 306; https://doi.org/10.3390/antibiotics12020306 - 02 Feb 2023

Cited by 6 | Viewed by 1421

Abstract

Periodontal disease (PD) is multifactorial oral disease that damages tooth-supporting tissue. PD treatment includes proper oral hygiene, deep cleaning, antibiotics therapy, and surgery. Despite the availability of basic treatments, some of these are rendered undesirable in PD treatment due to side effects and [...] Read more.

Periodontal disease (PD) is multifactorial oral disease that damages tooth-supporting tissue. PD treatment includes proper oral hygiene, deep cleaning, antibiotics therapy, and surgery. Despite the availability of basic treatments, some of these are rendered undesirable in PD treatment due to side effects and expense. Therefore, the aim of the present study is to develop novel molecules to combat the PD triggering pathogens. The study involved the synthesis of 4-((5-(substituted-phenyl)-1,3,4-oxadiazol-2-yl)methoxy)benzamidine (5a-e), by condensation of 2-(4-carbamimidoylphenoxy)acetohydrazide (3) with different aromatic acids; and synthesis of 4-((4-(substituted benzylideneamino)-4H-1,2,4-triazol-3-yl)methoxy)benzamidine (6a-b) by treatment of compound 3 with CS₂ followed by hydrazination and a Schiff reaction with different aromatic aldehydes. Synthesized compounds were characterized based on the NMR, FTIR, and mass spectrometric data. To assess the effectiveness of the newly synthesized compound in PD, new compounds were subjected to antimicrobial evaluation against P. gingivalis and E. coli using the micro-broth dilution method. Synthesized compounds were also subjected to cytotoxicity evaluation against HEK-293 cells using an MTT assay. The present study revealed the successful synthesis of heterocyclic derivatives of benzamidine with significant inhibitory potential against P. gingivalis and E. coli. Synthesized compounds exhibited minimal to the absence of cytotoxicity. Significant antimicrobial potential and least/no cytotoxicity of new heterocyclic analogs of benzamidine against PD-triggering bacteria supports their potential application in PD treatment. Full article

(This article belongs to the Special Issue Molecular Methods in Antibiotics Discovery)

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18 pages, 2453 KiB

Open AccessArticle

New Ionic Liquid Microemulsion-Mediated Synthesis of Silver Nanoparticles for Skin Bacterial Infection Treatments

by Fayez Althobaiti, Ola A. Abu Ali, Islam Kamal, Mohammad Y. Alfaifi, Ali A. Shati, Eman Fayad, Serag Eldin I. Elbehairi, Reda F. M. Elshaarawy and W. Abd El-Fattah

Antibiotics 2023, 12(2), 247; https://doi.org/10.3390/antibiotics12020247 - 25 Jan 2023

Cited by 3 | Viewed by 1431

Abstract

This work reports a new approach for the synthesis of extremely small monodispersed silver nanoparticles (AgNPs) (2.9–1.5) by reduction of silver nitrate in a new series of benzyl alkyl imidazolium ionic liquids (BAIILs)-based microemulsions (3a–f) as media and stabilizing agents. Interestingly, AgNPs isolated [...] Read more.

This work reports a new approach for the synthesis of extremely small monodispersed silver nanoparticles (AgNPs) (2.9–1.5) by reduction of silver nitrate in a new series of benzyl alkyl imidazolium ionic liquids (BAIILs)-based microemulsions (3a–f) as media and stabilizing agents. Interestingly, AgNPs isolated from the IILMEs bearing the bulkiest substituents (tert-butyl and n-butyl) (3f) displayed almost no nanoparticle agglomeration. In an in vitro antibacterial test against ESKAPE pathogens, all AgNPs-BAIILs had potent antibiotic activity, as reflected by antibacterial efficiency indices. Furthermore, when compared to other nanoparticles, these were the most effective in preventing biofilm formation by the tested bacterial strains. Moreover, the MTT assay was used to determine the cytotoxicity of novel AgNPs-BAIILs on healthy human skin fibroblast (HSF) cell lines. The MTT assay revealed that novel AgNPs-BAIILs showed no significant toxic effects on the healthy cells. Thus, the novel AgNPs-BAIILs microemulsions could be used as safe antibiotics for skin bacterial infection treatments. AgNPs isolated from BAIIL (3c) was found to be the most effective antibiotic of the nanoparticles examined. Full article

(This article belongs to the Special Issue Molecular Methods in Antibiotics Discovery)

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27 pages, 874 KiB

Open AccessArticle

Synthesis and Development of N-2,5-Dimethylphenylthioureido Acid Derivatives as Scaffolds for New Antimicrobial Candidates Targeting Multidrug-Resistant Gram-Positive Pathogens

by Povilas Kavaliauskas, Birutė Grybaitė, Rita Vaickelionienė, Birutė Sapijanskaitė-Banevič, Kazimieras Anusevičius, Agnė Kriaučiūnaitė, Gabrielė Smailienė, Vidmantas Petraitis, Rūta Petraitienė, Ethan Naing, Andrew Garcia and Vytautas Mickevičius

Antibiotics 2023, 12(2), 220; https://doi.org/10.3390/antibiotics12020220 - 20 Jan 2023

Cited by 1 | Viewed by 1838

Abstract

The growing antimicrobial resistance to last-line antimicrobials among Gram-positive pathogens remains a major healthcare emergency worldwide. Therefore, the search for new small molecules targeting multidrug-resistant pathogens remains of great importance. In this paper, we report the synthesis and in vitro antimicrobial activity characterisation [...] Read more.

The growing antimicrobial resistance to last-line antimicrobials among Gram-positive pathogens remains a major healthcare emergency worldwide. Therefore, the search for new small molecules targeting multidrug-resistant pathogens remains of great importance. In this paper, we report the synthesis and in vitro antimicrobial activity characterisation of novel thiazole derivatives using representative Gram-negative and Gram-positive strains, including tedizolid/linezolid-resistant S. aureus, as well as emerging fungal pathogens. The 4-substituted thiazoles 3h, and 3j with naphthoquinone-fused thiazole derivative 7 with excellent activity against methicillin and tedizolid/linezolid-resistant S. aureus. Moreover, compounds 3h, 3j and 7 showed favourable activity against vancomycin-resistant E. faecium. Compounds 9f and 14f showed broad-spectrum antifungal activity against drug-resistant Candida strains, while ester 8f showed good activity against Candida auris which was greater than fluconazole. Collectively, these data demonstrate that N-2,5-dimethylphenylthioureido acid derivatives could be further explored as novel scaffolds for the development of antimicrobial candidates targeting Gram-positive bacteria and drug-resistant pathogenic fungi. Full article

(This article belongs to the Special Issue Molecular Methods in Antibiotics Discovery)

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14 pages, 2032 KiB

Open AccessArticle

Tricyclic Fused Lactams by Mukaiyama Cyclisation of Phthalimides and Evaluation of their Biological Activity

by Lewis T. Ibbotson, Kirsten E. Christensen, Miroslav Genov, Alexander Pretsch, Dagmar Pretsch and Mark G. Moloney

Antibiotics 2023, 12(1), 9; https://doi.org/10.3390/antibiotics12010009 - 21 Dec 2022

Viewed by 1222

Abstract

We report that phthalimides may be cyclized using a Mukaiyama-type aldol coupling to give variously substituted fused lactam (1,2,3,9b-tetrahydro-5H-pyrrolo[2,1-a]isoindol-5-one) systems. This novel process shows a high level of regioselectivity for o-substituted phthalimides, dictated by steric and electronic factors, [...] Read more.

We report that phthalimides may be cyclized using a Mukaiyama-type aldol coupling to give variously substituted fused lactam (1,2,3,9b-tetrahydro-5H-pyrrolo[2,1-a]isoindol-5-one) systems. This novel process shows a high level of regioselectivity for o-substituted phthalimides, dictated by steric and electronic factors, but not for m-substituted phthalimides. The initial aldol adduct is prone to elimination, giving 2,3-dihydro-5H-pyrrolo[2,1-a]isoindol-5-ones, and the initial cyclisation can be conducted in such a way that aldol cyclisation-elimination is achievable in a one-pot approach. The 2,3-dihydro-5H-pyrrolo[2,1-a]isoindol-5-ones possess cross conjugation and steric effects which significantly influence the reactivity of several functional groups, but conditions suitable for epoxidation, ester hydrolysis and amide formation, and reduction, which provide for ring manipulation, were identified. Many of the derived lactam systems, and especially the eliminated systems, show low solubility, which compromises biological activity, although in some cases, antibacterial and cytotoxic activity was found, and this new class of small molecule provides a useful skeleton for further elaboration and study. Full article

(This article belongs to the Special Issue Molecular Methods in Antibiotics Discovery)

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16 pages, 3482 KiB

Open AccessArticle

Development of 4-[4-(Anilinomethyl)-3-phenyl-pyrazol-1-yl] Benzoic Acid Derivatives as Potent Anti-Staphylococci and Anti-Enterococci Agents

by Hansa Raj KC, David F. Gilmore and Mohammad A. Alam

Antibiotics 2022, 11(7), 939; https://doi.org/10.3390/antibiotics11070939 - 13 Jul 2022

Cited by 6 | Viewed by 1824

Abstract

From a library of compounds, 11 hit antibacterial agents have been identified as potent anti-Gram-positive bacterial agents. These pyrazole derivatives are active against two groups of pathogens, staphylococci and enterococci, with minimum inhibitory concentration (MIC) values as low as 0.78 μg/mL. These potent [...] Read more.

From a library of compounds, 11 hit antibacterial agents have been identified as potent anti-Gram-positive bacterial agents. These pyrazole derivatives are active against two groups of pathogens, staphylococci and enterococci, with minimum inhibitory concentration (MIC) values as low as 0.78 μg/mL. These potent compounds showed bactericidal action, and some were effective at inhibiting and eradicating Staphylococcus aureus and Enterococcus faecalis biofilms. Real-time biofilm inhibition by the potent compounds was studied, by using Bioscreen C. These lead compounds were also very potent against S. aureus persisters as compared to controls, gentamycin and vancomycin. In multiple passage studies, bacteria developed little resistance to these compounds (no more than 2 × MIC). The plausible mode of action of the lead compounds is the permeabilization of the cell membrane determined by flow cytometry and protein leakage assays. With the detailed antimicrobial studies, both in planktonic and biofilm contexts, some of these potent compounds have the potential for further antimicrobial drug development. Full article

(This article belongs to the Special Issue Molecular Methods in Antibiotics Discovery)

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16 pages, 12342 KiB

Open AccessArticle

Synergistic Antifungal Activity of Synthetic Peptides and Antifungal Drugs against Candida albicans and C. parapsilosis Biofilms

by Leandro P. Bezerra, Cleverson D. T. Freitas, Ayrles F. B. Silva, Jackson L. Amaral, Nilton A. S. Neto, Rafael G. G. Silva, Aura L. C. Parra, Gustavo H. Goldman, Jose T. A. Oliveira, Felipe P. Mesquita and Pedro F. N. Souza

Antibiotics 2022, 11(5), 553; https://doi.org/10.3390/antibiotics11050553 - 21 Apr 2022

Cited by 5 | Viewed by 2070

Abstract

C. albicans and C. parapsilosis are biofilm-forming yeasts responsible for bloodstream infections that can cause death. Synthetic antimicrobial peptides (SAMPs) are considered to be new weapons to combat these infections, alone or combined with drugs. Here, two SAMPs, called Mo-CBP₃-PepI [...] Read more.

C. albicans and C. parapsilosis are biofilm-forming yeasts responsible for bloodstream infections that can cause death. Synthetic antimicrobial peptides (SAMPs) are considered to be new weapons to combat these infections, alone or combined with drugs. Here, two SAMPs, called Mo-CBP₃-PepI and Mo-CBP₃-PepIII, were tested alone or combined with nystatin (NYS) and itraconazole (ITR) against C. albicans and C. parapsilosis biofilms. Furthermore, the mechanism of antibiofilm activity was evaluated by fluorescence and scanning electron microscopies. When combined with SAMPs, the results revealed a 2- to 4-fold improvement of NYS and ITR antibiofilm activity. Microscopic analyses showed cell membrane and wall damage and ROS overproduction, which caused leakage of internal content and cell death. Taken together, these results suggest the potential of Mo-CBP₃-PepI and Mo-CBP₃-PepIII as new drugs and adjuvants to increase the activity of conventional drugs for the treatment of clinical infections caused by C. albicans and C. parapsilosis. Full article

(This article belongs to the Special Issue Molecular Methods in Antibiotics Discovery)

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Review

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22 pages, 1920 KiB

Open AccessReview

Antisense and Functional Nucleic Acids in Rational Drug Development

by Robert Penchovsky, Antoniya V. Georgieva, Vanya Dyakova, Martina Traykovska and Nikolet Pavlova

Antibiotics 2024, 13(3), 221; https://doi.org/10.3390/antibiotics13030221 - 27 Feb 2024

Viewed by 1202

Abstract

This review is focused on antisense and functional nucleic acid used for completely rational drug design and drug target assessment, aiming to reduce the time and money spent and increase the successful rate of drug development. Nucleic acids have unique properties that play [...] Read more.

This review is focused on antisense and functional nucleic acid used for completely rational drug design and drug target assessment, aiming to reduce the time and money spent and increase the successful rate of drug development. Nucleic acids have unique properties that play two essential roles in drug development as drug targets and as drugs. Drug targets can be messenger, ribosomal, non-coding RNAs, ribozymes, riboswitches, and other RNAs. Furthermore, various antisense and functional nucleic acids can be valuable tools in drug discovery. Many mechanisms for RNA-based control of gene expression in both pro-and-eukaryotes and engineering approaches open new avenues for drug discovery with a critical role. This review discusses the design principles, applications, and prospects of antisense and functional nucleic acids in drug delivery and design. Such nucleic acids include antisense oligonucleotides, synthetic ribozymes, and siRNAs, which can be employed for rational antibacterial drug development that can be very efficient. An important feature of antisense and functional nucleic acids is the possibility of using rational design methods for drug development. This review aims to popularize these novel approaches to benefit the drug industry and patients. Full article

(This article belongs to the Special Issue Molecular Methods in Antibiotics Discovery)

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13 pages, 1439 KiB

Open AccessReview

Carbonic Anhydrase Inhibitors as Novel Antibacterials in the Era of Antibiotic Resistance: Where Are We Now?

by Alessio Nocentini, Clemente Capasso and Claudiu T. Supuran

Antibiotics 2023, 12(1), 142; https://doi.org/10.3390/antibiotics12010142 - 10 Jan 2023

Cited by 12 | Viewed by 2179

Abstract

Resistance to antibiotic treatment developed by bacteria in humans and animals occurs when the microorganisms resist treatment with clinically approved antibiotics. Actions must be implemented to stop the further development of antibiotic resistance and the subsequent emergence of superbugs. Medication repurposing/repositioning is one [...] Read more.

Resistance to antibiotic treatment developed by bacteria in humans and animals occurs when the microorganisms resist treatment with clinically approved antibiotics. Actions must be implemented to stop the further development of antibiotic resistance and the subsequent emergence of superbugs. Medication repurposing/repositioning is one strategy that can help find new antibiotics, as it speeds up drug development phases. Among them, the Zn²⁺ ion binders, such as sulfonamides and their bioisosteres, are considered the most promising compounds to obtain novel antibacterials, thus avoiding antibiotic resistance. Sulfonamides and their bioisosteres have drug-like properties well-known for decades and are suitable lead compounds for developing new pharmacological agent families for inhibiting carbonic anhydrases (CAs). CAs are a superfamily of metalloenzymes catalyzing the reversible reaction of CO₂ hydration to HCO₃⁻ and H⁺, being present in most bacteria in multiple genetic families (α-, β-, γ- and ι-classes). These enzymes, acting as CO₂ transducers, are promising drug targets because their activity influences microbe proliferation, biosynthetic pathways, and pathogen persistence in the host. In their natural or slightly modified scaffolds, sulfonamides/sulfamates/sulamides inhibit CAs in vitro and in vivo, in mouse models infected with antibiotic-resistant strains, confirming thus their role in contrasting bacterial antibiotic resistance. Full article

(This article belongs to the Special Issue Molecular Methods in Antibiotics Discovery)

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