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1.
Int J Mol Sci ; 25(13)2024 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-39000138

RESUMO

The ongoing battle against viral pandemics continues, with the possibility of future outbreaks. The search for effective antiviral compounds that can combat a diverse range of viruses continues to be a focal point of research. This study investigated the efficacy of two natural antimicrobial peptides (AMPs) (lactoferricin and LL-37), two synthetic AMPs (melimine and Mel4), and nine AMP mimics (758, 1091, 1096, 1083, 610, NAPL, 3-BIPL, 4-BIPL, and Sau-22) against influenza A virus strains H1N1 and H3N2, human adenovirus 5 (HAdV-5), and murine norovirus 1 (MNV-1). These compounds were tested using virus pre-treatment, cell pre-treatment, or post-cell entry treatment assays, electron microscopy, and circular dichroism (CD), alongside evaluations of cytotoxicity against the host cells. After virus pre-treatment, the AMP mimics 610 and Sau-22 had relatively low IC50 values for influenza strains H1N1 (2.35 and 6.93 µM, respectively) and H3N2 (3.7 and 5.34 µM, respectively). Conversely, natural and synthetic AMPs were not active against these strains. For the non-enveloped viruses, the AMP Mel4 and mimic 1083 had moderate activity against HAdV-5 (Mel4 IC50 = 47.4 µM; 1083 IC50 = 47.2 µM), whereas all AMPs, but none of the mimics, were active against norovirus (LL-37 IC50 = 4.2 µM; lactoferricin IC50 = 23.18 µM; melimine IC50 = 4.8 µM; Mel4 IC50 = 8.6 µM). Transmission electron microscopy demonstrated that the mimics targeted the outer envelope of influenza viruses, while the AMPs targeted the capsid of non-enveloped viruses. CD showed that Mel4 adopted an α-helical structure in a membrane mimetic environment, but mimic 758 remained unstructured. The diverse activity against different virus groups is probably influenced by charge, hydrophobicity, size, and, in the case of natural and synthetic AMPs, their secondary structure. These findings underscore the potential of peptides and mimics as promising candidates for antiviral therapeutics against both enveloped and non-enveloped viruses.


Assuntos
Antivirais , Norovirus , Norovirus/efeitos dos fármacos , Animais , Humanos , Camundongos , Antivirais/farmacologia , Antivirais/química , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/fisiologia , Peptídeos Antimicrobianos/farmacologia , Peptídeos Antimicrobianos/química , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Cães , Adenoviridae/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Células Madin Darby de Rim Canino , Peptídeos Catiônicos Antimicrobianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/química
2.
Cont Lens Anterior Eye ; : 102246, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38851947

RESUMO

PURPOSE: Myopia (short-sightedness) is a growing vision problem worldwide. Currently atropine eye drops are used to control the progression of myopia but these suffer from potential lack of bioavailability and low ocular residence time. Commercially available myopia control contact lenses are also used to limit myopia progression, but neither atropine nor contact lenses individually completely stop progression. Development of myopia control contact lenses which could deliver therapeutic doses of atropine is thus desirable and may provide increased efficacy. This study was designed to explore the feasibility of attaching atropine to etafilcon A contact lenses through an esterification reaction. METHODS: Carboxylic acid groups on etafilcon A contact lenses were quantified using Toluidine Blue O. The carboxylic acid groups in etafilcon A contact lenses were activated using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC-HCl) and N-hydroxysuccinimide (NHS) crosslinkers after which atropine was added to undergo potential binding via esterification. Atropine was released from lenses by alkaline hydrolysis. Reverse phase high performance liquid chromatography (HPLC) was used to detect and quantify the released atropine and its degradation products in solution. Contact lenses that had not been activated by EDC-NHS (controls) were also examined to determine the amount of atropine that could be absorbed rather than chemically bound to lenses. RESULTS: Each etafilcon A contact lens contained 741.1 ± 5.5 µg carboxylic acid groups which may be available for esterification. HPLC had a limit of detection for atropine of 0.38 µg/mL and for tropic acid, an atropine degradation product, of 0.80 µg/mL. The limits of quantification were 1.16 µg/mL for atropine and 2.41 µg/mL for tropic acid in NH4HCO3. The etafilcon A lenses adsorbed up to 7.69 µg atropine when incubated in a 5 mg/mL atropine solution for 24 h. However, there was no evidence that atropine could be chemically linked to the lenses, as washing in a high concentration of NaCl removed all the atropine from the contact lenses with no atropine being subsequently released from the lenses after incubating in 0.01 N NH4HCO3. CONCLUSIONS: Etafilcon A contact lenses contain free carboxylic acids which may be an appropriate option for attaching drugs such as atropine. Etafilcon A lenses adsorbed up to 7.69 µg atropine, which would be more than enough to deliver atropine to eyes to control myopia. However, atropine could not be chemically bound to the carboxylic acids of the etafilcon A lenses using this methodology.

3.
Bioorg Chem ; 147: 107334, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38583251

RESUMO

Building upon our previous study on peptoid-based antibacterials which showed good activity against Gram-positive bacteria only, herein we report the synthesis of 34 dimeric peptoid compounds and the investigation of their activity against Gram-positive and Gram-negative pathogens. The newly designed peptoids feature a di-hydrophobic moiety incorporating phenyl, bromo-phenyl, and naphthyl groups, combined with variable lengths of cationic units such as amino and guanidine groups. The study also underscores the pivotal interplay between hydrophobicity and cationicity in optimizing efficacy against specific bacteria. The bromophenyl dimeric guanidinium peptoid compound 10j showed excellent activity against S. aureus 38 and E. coli K12 with MIC of 0.8 µg mL-1 and 6.2 µg mL-1, respectively. Further investigation into the mechanism of action revealed that the antibacterial effect might be attributed to the disruption of bacterial cell membranes, as suggested by tethered bilayer lipid membranes (tBLMs) and cytoplasmic membrane permeability studies. Notably, these promising antibacterial agents exhibited negligible toxicity against mammalian red blood cells. Additionally, the study explored the potential of 12 active compounds to disrupt established biofilms of S. aureus 38. The most effective biofilm disruptors were ethyl and octyl-naphthyl guanidinium peptoids (10c and 10 k). These compounds 10c and 10 k disrupted the established biofilms of S. aureus 38 with 51 % at 4x MIC (MIC = 17.6 µg mL-1 and 11.2 µg mL-1) and 56 %-58 % at 8x MIC (MIC = 35.2 µg mL-1 and 22.4 µg mL-1) respectively. Overall, this research contributes insights into the design principles of cationic dimeric peptoids and their antibacterial activity, with implications for the development of new antibacterial compounds.


Assuntos
Antibacterianos , Biofilmes , Testes de Sensibilidade Microbiana , Peptoides , Staphylococcus aureus , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Peptoides/química , Peptoides/farmacologia , Peptoides/síntese química , Biofilmes/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Estrutura Molecular , Relação Dose-Resposta a Droga , Dimerização , Escherichia coli/efeitos dos fármacos , Humanos , Eritrócitos/efeitos dos fármacos
4.
Cont Lens Anterior Eye ; 47(3): 102154, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38523013

RESUMO

Dry eye disease is a progressive prevalent ocular surface disorder that arises from various factors and is characterized by insufficient quality and/or quantity of tears. The underlying pathophysiology is intricate and can progress to chronic, difficult-to-treat conditions. Multiple strategies and therapeutic approaches are utilized in its management that target one or more etiopathological components of dry eyes, which may include aqueous tear deficiency or evaporative dry eyes. The primary focus of this paper is on treatment alternatives that utilize lipids for the treatment of evaporative dry eyes. This may arise from either abnormal lipid production or inadequate lipid spreading caused by meibomian gland dysfunction. The hypothesis behind the development of these lipid-containing eye drops is that if they can imitate the lipid layer, they may be able to help in the management of the signs and symptoms of evaporative dry eyes. The lipids used in commercial formulations for dry eyes are mineral oil, castor oil, phospholipids, omega-3 fatty acid, and medium-chain triglycerides. The literature suggests the potential of lipid-containing eye drops to alleviate some of the signs and symptoms and enhance the quality of life for individuals suffering from evaporative dry eyes.


Assuntos
Síndromes do Olho Seco , Lipídeos , Soluções Oftálmicas , Lágrimas , Síndromes do Olho Seco/tratamento farmacológico , Síndromes do Olho Seco/fisiopatologia , Humanos , Lágrimas/química , Lágrimas/metabolismo , Perda Insensível de Água/efeitos dos fármacos
5.
Cont Lens Anterior Eye ; 47(2): 102124, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38341309

RESUMO

BACKGROUND: Ocular infections caused by antibiotic-resistant pathogens can result in partial or complete vision loss. The development of pan-resistant microbial strains poses a significant challenge for clinicians as there are limited antimicrobial options available. Synthetic peptoids, which are sequence-specific oligo-N-substituted glycines, offer potential as alternative antimicrobial agents to target multidrug-resistant bacteria. METHODS: The antimicrobial activity of synthesised peptoids against multidrug-resistant (MDR) ocular pathogens was evaluated using the microbroth dilution method. Hemolytic propensity was assessed using mammalian erythrocytes. Peptoids were also incubated with proteolytic enzymes, after which their minimum inhibitory activity against bacteria was re-evaluated. RESULTS: Several alkylated and brominated peptoids showed good inhibitory activity against multidrug-resistant Pseudomonas aeruginosa strains at concentrations of ≤15 µg mL-1 (≤12 µM). Similarly, most brominated compounds inhibited the growth of methicillin-resistant Staphylococcus aureus at 1.9 to 15 µg mL-1 (12 µM). The N-terminally alkylated peptoids caused less toxicity to erythrocytes. The peptoid denoted as TM5 had a high therapeutic index, being non-toxic to either erythrocytes or corneal epithelial cells, even at 15 to 22 times its MIC. Additionally, the peptoids were resistant to protease activity. CONCLUSIONS: Peptoids studied here demonstrated potent activity against various multidrug-resistant ocular pathogens. Their properties make them promising candidates for controlling vision-related morbidity associated with eye infections by antibiotic-resistant strains.


Assuntos
Anti-Infecciosos , Staphylococcus aureus Resistente à Meticilina , Peptoides , Animais , Humanos , Peptoides/farmacologia , Testes de Sensibilidade Microbiana , Anti-Infecciosos/farmacologia , Antibacterianos/farmacologia , Mamíferos
6.
J Pept Sci ; 30(6): e3560, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38262069

RESUMO

The rise of antimicrobial resistance and multi-drug resistant pathogens has necessitated explorations for novel antibiotic agents as the discovery of conventional antibiotics is becoming economically less viable and technically more challenging for biopharma. Antimicrobial peptides (AMPs) have emerged as a promising alternative because of their particular mode of action, broad spectrum and difficulty that microbes have in becoming resistant to them. The AMPs bacitracin, gramicidin, polymyxins and daptomycin are currently used clinically. However, their susceptibility to proteolytic degradation, toxicity profile, and complexities in large-scale manufacture have hindered their development. To improve their proteolytic stability, methods such as integrating non-canonical amino acids (ncAAs) into their peptide sequence have been adopted, which also improves their potency and spectrum of action. The benefits of ncAA incorporation have been made possible by solid-phase peptide synthesis. However, this method is not always suitable for commercial production of AMPs because of poor yield, scale-up difficulties, and its non-'green' nature. Bioincorporation of ncAA as a method of integration is an emerging field geared towards tackling the challenges of solid-phase synthesis as a green, cheaper, and scalable alternative for commercialisation of AMPs. This review focusses on the bioincorporation of ncAAs; some challenges associated with the methods are outlined, and notes are given on how to overcome these challenges. The review focusses particularly on addressing two key challenges: AMP cytotoxicity towards microbial cell factories and the uptake of ncAAs that are unfavourable to them. Overcoming these challenges will draw us closer to a greater yield and an environmentally friendly and sustainable approach to make AMPs more druggable.


Assuntos
Aminoácidos , Peptídeos Antimicrobianos , Aminoácidos/química , Aminoácidos/metabolismo , Peptídeos Antimicrobianos/química , Peptídeos Antimicrobianos/farmacologia , Humanos , Antibacterianos/farmacologia , Antibacterianos/química , Técnicas de Síntese em Fase Sólida/métodos , Testes de Sensibilidade Microbiana
7.
Int J Mol Sci ; 24(19)2023 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-37834415

RESUMO

Bacteria readily acquire resistance to traditional antibiotics, resulting in pan-resistant strains with no available treatment. Antimicrobial resistance is a global challenge and without the development of effective antimicrobials, the foundation of modern medicine is at risk. Combination therapies such as antibiotic-antibiotic and antibiotic-adjuvant combinations are strategies used to combat antibiotic resistance. Current research focuses on antimicrobial peptidomimetics as adjuvant compounds, due to their promising activity against antibiotic-resistant bacteria. Here, for the first time we demonstrate that antibiotic-peptidomimetic combinations mitigate the development of antibiotic resistance in Staphylococcus aureus and Pseudomonas aeruginosa. When ciprofloxacin and gentamicin were passaged individually at sub-inhibitory concentrations for 10 days, the minimum inhibitory concentrations (MICs) increased up to 32-fold and 128-fold for S. aureus and P. aeruginosa, respectively. In contrast, when antibiotics were passaged in combination with peptidomimetics (Melimine, Mel4, RK758), the MICs of both antibiotics and peptidomimetics remained constant, indicating these combinations were able to mitigate the development of antibiotic-resistance. Furthermore, antibiotic-peptidomimetic combinations demonstrated synergistic activity against both Gram-positive and Gram-negative bacteria, reducing the concentration needed for bactericidal activity. This has significant potential clinical applications-including preventing the spread of antibiotic-resistant strains in hospitals and communities, reviving ineffective antibiotics, and lowering the toxicity of antimicrobial chemotherapy.


Assuntos
Anti-Infecciosos , Peptidomiméticos , Antibacterianos/farmacologia , Ciprofloxacina/farmacologia , Peptidomiméticos/farmacologia , Gentamicinas/farmacologia , Staphylococcus aureus , Staphylococcus , Bactérias Gram-Negativas , Bactérias Gram-Positivas , Anti-Infecciosos/farmacologia , Pseudomonas aeruginosa , Bactérias , Testes de Sensibilidade Microbiana
8.
Antibiotics (Basel) ; 12(9)2023 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-37760732

RESUMO

The development of potent antiviral agents is of utmost importance to combat the global burden of viral infections. Traditional antiviral drug development involves targeting specific viral proteins, which may lead to the emergence of resistant strains. To explore alternative strategies, we investigated the antiviral potential of antimicrobial peptidomimetic compounds. In this study, we evaluated the antiviral potential of 17 short anthranilamide-based peptidomimetic compounds against two viruses: Murine hepatitis virus 1 (MHV-1) which is a surrogate of human coronaviruses and herpes simplex virus 1 (HSV-1). The half-maximal inhibitory concentration (IC50) values of these compounds were determined in vitro to assess their potency as antiviral agents. Compounds 11 and 14 displayed the most potent inhibitory effects with IC50 values of 2.38 µM, and 6.3 µM against MHV-1 while compounds 9 and 14 showed IC50 values of 14.8 µM and 13 µM against HSV-1. Multiple antiviral assessments and microscopic images obtained through transmission electron microscopy (TEM) collectively demonstrated that these compounds exert a direct influence on the viral envelope. Based on this outcome, it can be concluded that peptidomimetic compounds could offer a new approach for the development of potent antiviral agents.

9.
Peptides ; 166: 171024, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37172781

RESUMO

Viral epidemics are occurring frequently, and the COVID-19 viral pandemic has resulted in at least 6.5 million deaths worldwide. Although antiviral therapeutics are available, these may not have sufficient effect. The emergence of resistant or novel viruses requires new therapies. Cationic antimicrobial peptides are agents of the innate immune system that may offer a promising solution to viral infections. These peptides are gaining attention as possible therapies for viral infections or for use as prophylactic agents to prevent viral spread. This narrative review examines antiviral peptides, their structural features, and mechanism of activity. A total of 156 cationic antiviral peptides were examined for information of their mechanism of action against both enveloped and non-enveloped viruses. Antiviral peptides can be isolated from various natural sources or can be generated synthetically. The latter tend to be more specific and effective and can be made to have a broad spectrum of activity with minimal side effects. Their unique properties of being positively charged and amphipathic enable their main mode of action which is to target and disrupt viral lipid envelopes, thereby inhibiting viral entry and replication. This review offers a comprehensive summary of the current understanding of antiviral peptides, which could potentially aid in the design and creation of novel antiviral medications.


Assuntos
COVID-19 , Viroses , Vírus , Humanos , Antivirais/farmacologia , Antivirais/uso terapêutico , Peptídeos Catiônicos Antimicrobianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/uso terapêutico , Viroses/tratamento farmacológico
10.
Antibiotics (Basel) ; 12(3)2023 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-36978452

RESUMO

There is a pressing need to develop new antimicrobials to help combat the increase in antibiotic resistance that is occurring worldwide. In the current research, short amphiphilic antibacterial and antibiofilm agents were produced by tuning the hydrophobic and cationic groups of anthranilamide peptidomimetics. The attachment of a lysine cationic group at the tail position increased activity against E. coli by >16-fold (from >125 µM to 15.6 µM) and greatly reduced cytotoxicity against mammalian cells (from ≤20 µM to ≥150 µM). These compounds showed significant disruption of preformed biofilms of S. aureus at micromolar concentrations.

12.
Bioorg Chem ; 130: 106226, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36332317

RESUMO

It is well established that the quorum sensing (QS) in Pseudomonas aeruginosa is primarily responsible for the synthesis and the release of several virulence factors including pyocyanin and are involved in biofilm formation. In the Pseudomonas quinolone signal (PQS) system, autoinducers such as PQS and HHQ bind and activate the transcription regulator protein receptor PqsR (MvfR). Targeting PqsR with competitive inhibitors could be a promising strategy to inhibit QS in P. aeruginosa to overcome antimicrobial resistance. In this study, we have designed and synthesized a series of novel quinazolinone disulfide-containing competitive inhibitor of PqsR. The most potent analogue 8q efficiently inhibited the pqs system with an IC50 value of 4.5 µM. It also showed complete suppression of pyocyanin production and a significant reduction in biofilm formation by P. aeruginosa (PAO1) with low cytotoxicity. Additionally, 8q produced synergy in combination with known antibiotics such as ciprofloxacin and tobramycin. Finally, molecular docking analysis suggested that compound 8q could bind with the ligand-binding domain of PqsR in a similar fashion to the native ligand.


Assuntos
Pseudomonas aeruginosa , Percepção de Quorum , Pseudomonas aeruginosa/fisiologia , Piocianina , Ligantes , Simulação de Acoplamento Molecular , Quinazolinonas/farmacologia , Quinazolinonas/metabolismo , Dissulfetos/farmacologia , Biofilmes , Proteínas de Bactérias/metabolismo
13.
Sci Rep ; 12(1): 22259, 2022 12 23.
Artigo em Inglês | MEDLINE | ID: mdl-36564414

RESUMO

In this study, we prepared antibacterial hydrogels through the self-assembly of naphthyl anthranilamide (NaA) capped amino acid based cationic peptide mimics. These ultra-short cationic peptide mimics were rationally designed with NaA as a capping group, L-phenylalanine, a short aliphatic linker, and a cationic group. The synthesized peptide mimics efficiently formed hydrogels with minimum gel concentrations between 0.1 and 0.3%w/v. The resulting hydrogels exhibited desirable viscoelastic properties which can be tuned by varying the cationic group, electronegative substituent, or counter anion. Importantly, nanofibers from the NaA-capped cationic hydrogels were found to be the source of hydrogels' potent bacteriacidal actvity against both Gram-positive and Gram-negative bacteria while remaining non-cytotoxic. These intrinsically antibacterial hydrogels are ideal candidates for further development in applications where bacterial contamination is problematic.


Assuntos
Antibacterianos , Hidrogéis , Antibacterianos/farmacologia , Antibacterianos/química , Hidrogéis/química , Bactérias Gram-Negativas , Bactérias Gram-Positivas , Testes de Sensibilidade Microbiana , Peptídeos/química , Cátions
14.
Microorganisms ; 10(12)2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36557630

RESUMO

Acanthamoeba is a free-living protozoan known to cause keratitis most commonly, especially among contact lens wearers. Treatment of Acanthamoeba keratitis is challenging as Acanthamoeba can encyst from the active form, a trophozoite, into a hibernating cyst that is refractory to antibiotics and difficult to kill; therefore, there is a need for more effective anti-amoebic strategies. In this study, we have evaluated the anti-amoebic activity of the antimicrobial peptide mimic RK-758 against Acanthamoeba castellanii. RK-758 peptidomimetic was subjected to biological assays to investigate its amoebicidal, amoebistatic, anti-encystation, and anti-excystation effects on A. castellanii. The anti-amoebic activity of the peptide mimic RK-758 was compared with chlorhexidine against the Acanthamoeba castellanii ATCC30868 and Acanthamoeba castellanii 044 (a clinical strain) with the concentrations of both ranging from 125 µM down to 7.81 µM. All experiments were performed in duplicate with three independent replicates. The data were represented as mean ± SE and analysed using a two-sample t-test and two-tailed distributions. A p < 0.05 was considered statistically significant. The peptidomimetic RK-758 had anti-Acanthamoeba activity against both trophozoites and cysts in a dose-dependent manner. The RK-758 had amoebicidal and growth inhibitory activities of ≥50% at a concentration between 125 µM and 15.6 µM against the trophozoites of both Acanthamoeba strains. Inhibitory effects on the cyst formation and trophozoite re-emergence from cysts were noted at similar concentrations. Chlorhexidine had 50% activity at 7.81 µM and above against the trophozoites and cysts of both strains. In the haemolysis assay, the RK-758 lysed horse RBCs at concentrations greater than 50 µM whereas lysis occurred at concentrations greater than 125 µM for the chlorhexidine. The peptidomimetic RK-758, therefore, has activity against both the trophozoite and cyst forms of Acanthamoeba and has the potential to be further developed as an anti-microbial agent against Acanthamoeba. RK-758 may also have use as an anti-amoebic disinfectant in contact lens solutions.

15.
Antibiotics (Basel) ; 11(8)2022 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-36009943

RESUMO

Peptoids are peptidomimetics that have attracted considerable interest as a promising class of antimicrobials against multi-drug-resistant bacteria due to their resistance to proteolysis, bioavailability, and thermal stability compared to their corresponding peptides. Staphylococcus aureus is a significant contributor to infections worldwide and is a major pathogen in ocular infections (keratitis). S. aureus infections can be challenging to control and treat due to the development of multiple antibiotic resistance. This work describes short cationic peptoids with activity against S. aureus strains from keratitis. The peptoids were synthesized via acid amine-coupling between naphthyl-indole amine or naphthyl-phenyl amine with different amino acids to produce primary amines (series I), mono-guanidines (series II), tertiary amine salts (series III), quaternary ammonium salts (series IV), and di-guanidine (series V) peptoids. The antimicrobial activity of the peptoids was compared with ciprofloxacin, an antibiotic that is commonly used to treat keratitis. All new compounds were active against Staphylococcus aureus S.aureus 38. The most active compounds against S.aur38 were 20a and 22 with MIC = 3.9 µg mL−1 and 5.5 µg mL−1, respectively. The potency of these two active molecules was investigated against 12 S. aureus strains that were isolated from microbial keratitis. Compounds 20a and 22 were active against 12 strains with MIC = 3.2 µg mL−1 and 2.1 µg mL−1, respectively. There were two strains that were resistant to ciprofloxacin (Sa.111 and Sa.112) with MIC = 128 µg mL−1 and 256 µg mL−1, respectively. Compounds 12c and 13c were the most active against E. coli, with MIC > 12 µg mL−1. Cytoplasmic membrane permeability studies suggested that depolarization and disruption of the bacterial cell membrane could be a possible mechanism for antibacterial activity and the hemolysis studies toward horse red blood cells showed that the potent compounds are non-toxic at up to 50 µg mL−1.

16.
Curr Med Chem ; 30(1): 104-125, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35702780

RESUMO

Antibiotic resistance is a growing global health problem when the discovery and development of novel antibiotics are diminishing. Various strategies have been proposed to address the problem of growing antibacterial resistance. One such strategy is the development of hybrid antibiotics. These therapeutic systems have been designed for two or more pharmacophores of known antimicrobial agents. This review highlights the latest development of antibiotic hybrids comprising two antibiotics (cleavable and non-cleavable) and combinations of biocidal and novel compounds to treat bacterial infections. The approach of dual-acting hybrid compounds has a promising future in overcoming drug resistance in bacterial pathogens.


Assuntos
Anti-Infecciosos , Infecções Bacterianas , Humanos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Anti-Infecciosos/farmacologia , Infecções Bacterianas/tratamento farmacológico , Farmacorresistência Bacteriana , Bactérias
17.
Int J Mol Sci ; 23(9)2022 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-35563014

RESUMO

There is a significant and urgent need for the development of novel antibacterial agents to tackle the increasing incidence of antibiotic resistance. Cholic acid-based small molecular antimicrobial peptide mimics are reported as potential new leads to treat bacterial infection. Here, we describe the design, synthesis and biological evaluation of cholic acid-based small molecular antimicrobial peptide mimics. The synthesis of cholic acid analogues involves the attachment of a hydrophobic moiety at the carboxyl terminal of the cholic acid scaffold, followed by the installation of one to three amino acid residues on the hydroxyl groups present on the cholic acid scaffold. Structure-activity relationship studies suggest that the tryptophan moiety is important for high antibacterial activity. Moreover, a minimum of +2 charge is also important for antimicrobial activity. In particular, analogues containing lysine-like residues showed the highest antibacterial potency against Gram-positive S. aureus. All di-substituted analogues possess high antimicrobial activity against both Gram-positive S. aureus as well as Gram-negative E. coli and P. aeruginosa. Analogues 17c and 17d with a combination of these features were found to be the most potent in this study. These compounds were able to depolarise the bacterial membrane, suggesting that they are potential antimicrobial pore forming agents.


Assuntos
Antibacterianos , Anti-Infecciosos , Antibacterianos/química , Anti-Infecciosos/farmacologia , Peptídeos Antimicrobianos , Ácido Cólico/farmacologia , Escherichia coli , Testes de Sensibilidade Microbiana , Staphylococcus aureus , Relação Estrutura-Atividade
18.
Antibiotics (Basel) ; 11(3)2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-35326856

RESUMO

Transmission of pathogens present in the indoor air can occur through aerosols. This study evaluated the efficacy of an evaporated mix of essential oils to reduce the numbers of culturable aerosolized coronavirus, bacterium and fungus. The essential oil-containing gel was allowed to vaporize inside a glass chamber for 10 or 20 min. Aerosols of a surrogate of SARS-CoV-2, murine hepatitis coronavirus MHV-1, Escherichia coli or Aspergillus flavus spores were produced using a collision nebuliser and passed through the essential oil vapours, then collected on a six-stage Andersen sampler. The six-stages of the impact sampler capture aerosols in sizes ranging from 7 to 0.65 µm. The number of culturable microbes present in the aerosols collected in the different stages were enumerated and compared to the number of culturable microbes in control microbial aerosols that were not exposed to the evaporated essential oils. After 10 and 20 min evaporation, the essential oils reduced the numbers of culturable aerosolized coronavirus by 48% (log10 reduction = 0.3; p = 0.002 vs. control) and 53% (log10 reduction = 0.3; p = 0.001 vs. control), respectively. The essential oils vaporised for 10 min, reduced the number of viable E. coli by 51% (log10 reduction = 0.3; p = 0.032 vs. control). The Aspergillus flavus spores were mostly observed in the larger aerosols (7.00 µm to 2.10 µm) and the essential oils vaporised for 10 min reduced the number of viable spores by 72% (log10 reduction = 0.6; p = 0.008 vs. control). The vapours produced by a gel containing naturally occurring essential oils were able to significantly reduce the viable numbers of aerosolized coronavirus, bacteria and fungal spores. The antimicrobial gel containing the essential oils may be able to reduce aerosol transmission of microbes when used in domestic and workplace settings.

19.
Int J Mol Sci ; 23(6)2022 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-35328373

RESUMO

The prevention and treatment of biofilm-mediated infections remains an unmet clinical need for medical devices. With the increasing prevalence of antibiotic-resistant infections, it is important that novel approaches are developed to prevent biofilms forming on implantable medical devices. This study presents a versatile and simple polydopamine surface coating technique for medical devices, using a new class of antibiotics-antimicrobial peptidomimetics. Their unique mechanism of action primes them for activity against antibiotic-resistant bacteria and makes them suitable for covalent attachment to medical devices. This study assesses the anti-biofilm activity of peptidomimetics, characterises the surface chemistry of peptidomimetic coatings, quantifies the antibacterial activity of coated surfaces and assesses the biocompatibility of these coated materials. X-ray photoelectron spectroscopy and water contact angle measurements were used to confirm the chemical modification of coated surfaces. The antibacterial activity of surfaces was quantified for S. aureus, E. coli and P. aeruginosa, with all peptidomimetic coatings showing the complete eradication of S. aureus on surfaces and variable activity for Gram-negative bacteria. Scanning electron microscopy confirmed the membrane disruption mechanism of peptidomimetic coatings against E. coli. Furthermore, peptidomimetic surfaces did not lyse red blood cells, which suggests these surfaces may be biocompatible with biological fluids such as blood. Overall, this study provides a simple and effective antibacterial coating strategy that can be applied to biomaterials to reduce biofilm-mediated infections.


Assuntos
Anti-Infecciosos , Peptidomiméticos , Antibacterianos/química , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Biofilmes , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/farmacologia , Escherichia coli , Indóis , Peptidomiméticos/farmacologia , Polímeros , Pseudomonas aeruginosa , Staphylococcus aureus
20.
Int J Mol Sci ; 22(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34298964

RESUMO

The rapid emergence of drug-resistant bacteria is a major global health concern. Antimicrobial peptides (AMPs) and peptidomimetics have arisen as a new class of antibacterial agents in recent years in an attempt to overcome antibiotic resistance. A library of phenylglyoxamide-based small molecular peptidomimetics was synthesised by incorporating an N-alkylsulfonyl hydrophobic group with varying alkyl chain lengths and a hydrophilic cationic group into a glyoxamide core appended to phenyl ring systems. The quaternary ammonium iodide salts 16d and 17c showed excellent minimum inhibitory concentration (MIC) of 4 and 8 µM (2.9 and 5.6 µg/mL) against Staphylococcus aureus, respectively, while the guanidinium hydrochloride salt 34a showed an MIC of 16 µM (8.5 µg/mL) against Escherichia coli. Additionally, the quaternary ammonium iodide salt 17c inhibited 70% S. aureus biofilm formation at 16 µM. It also disrupted 44% of pre-established S. aureus biofilms at 32 µM and 28% of pre-established E. coli biofilms 64 µM, respectively. A cytoplasmic membrane permeability study indicated that the synthesised peptidomimetics acted via disruption and depolarisation of membranes. Moreover, the quaternary ammonium iodide salts 16d and 17c were non-toxic against human cells at their therapeutic dosages against S. aureus.


Assuntos
Antibacterianos , Biofilmes/efeitos dos fármacos , Escherichia coli/fisiologia , Peptidomiméticos , Staphylococcus aureus/fisiologia , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Biofilmes/crescimento & desenvolvimento , Peptidomiméticos/síntese química , Peptidomiméticos/química , Peptidomiméticos/farmacologia , Relação Estrutura-Atividade , Compostos de Sulfonilureia/síntese química , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/farmacologia
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