scholarly journals Novel Small-Molecule Hybrid-Antibacterial Agents against S. aureus and MRSA Strains

Molecules ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 61
Author(s):  
Robin Gehrmann ◽  
Tobias Hertlein ◽  
Elisa Hopke ◽  
Knut Ohlsen ◽  
Michael Lalk ◽  
...  
Keyword(s):  
Small Molecule ◽  
Antibacterial Agents ◽  
One Pot ◽  
Antibacterial Compounds ◽  
Lead Compounds ◽  
Mrsa Strains ◽  
Novel Structures

Ongoing resistance developments against antibiotics that also affect last-resort antibiotics require novel antibacterial compounds. Strategies to discover such novel structures have been dimerization or hybridization of known antibacterial agents. We found novel antibacterial agents by dimerization of indols and hybridization with carbazoles. They were obtained in a simple one-pot reaction as bisindole tetrahydrocarbazoles. Further oxidation led to bisindole carbazoles with varied substitutions of both the indole and the carbazole scaffold. Both the tetrahydrocarbazoles and the carbazoles have been evaluated in various S. aureus strains, including MRSA strains. Those 5-cyano substituted derivatives showed best activities as determined by MIC values. The tetrahydrocarbazoles partly exceed the activity of the carbazole compounds and thus the activity of the used standard antibiotics. Thus, promising lead compounds could be identified for further studies.

Discovery of a novel class of small-molecule antibacterial agents against Staphylococcus aureus

2021 ◽  
Author(s):  
David Kreutzer ◽  
Robin Gehrmann ◽  
Annámaria Kincses ◽  
Nikoletta Szemerédi ◽  
Gabriella Spengler ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antibacterial Activity ◽  
Small Molecule ◽  
Antibacterial Agents ◽  
Antibacterial Effects ◽  
Molecular Scaffold ◽  
Antibacterial Compounds ◽  
Aromatic Residue ◽  
Lead Compounds ◽  
Step Procedure

Background: With constantly increasing resistance against the known antibiotics, the search for novel antibacterial compounds is a challenge. The number of synthetic antibacterial agents is limited. Materials & methods: We discovered novel small-molecule antibacterial agents that are accessible via a simple two-step procedure. The evaluation against Staphylococcus aureus showed antibacterial effects depending on the substituent positioning at the residues of the molecular scaffold. Additionally, we investigated the potential of the compounds to increase the antibacterial activity of tetracycline. Results: The most effective antibacterial compounds possessed a 3-methoxy function at an aromatic residue. In combination with tetracycline, we found a strong effect for a few compounds in boosting the antibacterial activity, so the first promising lead compounds with dual activities could be identified.

Novel effective antibacterial small-molecules against Staphylococcus and Enterococcus strains

2020 ◽  
Vol 12 (13) ◽  
pp. 1205-1211
Author(s):  
Kaveh Yasrebi ◽  
Nico Schade ◽  
Emmanuel Tola Adeniyi ◽  
Björn Wecklein ◽  
Alba Ymeraj ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Antibacterial Drug ◽  
The Novel ◽  
One Pot ◽  
Drug Candidates ◽  
Lead Compounds ◽  
Ring Open ◽  
Novel Antibiotics

Background: Resistance developments against established antibiotics are an emerging problem for antibacterial therapies. Novel antibiotics are urgently needed. Materials & methods: We developed novel small-molecule antibacterials which are easily accessible in a simple one-pot synthesis. The central cyclopentaindole core is substituted with two indole residues. Various indole and cyclopentane substituents have been introduced. Additionally, first indole substituted propene compounds as ring-open variants of the cyclopentaindoles have been yielded and evaluated as antibacterials against Staphylococcus aureus and Enterococcus strains. Results: Most effective compounds have been those with a bromo cyclopentane and a chloro indole substitution. First lead compounds were identified with promising activities similar to that observed in vitro for last resort antibiotics, so that the novel compounds enriche the pool of perspective small-molecule antibacterial drug candidates.

scholarly journals Structural and functional conservation of the programmed −1 ribosomal frameshift signal of SARS-CoV-2

2020 ◽  
Author(s):  
Jamie A. Kelly ◽  
Alexandra N. Olson ◽  
Krishna Neupane ◽  
Sneha Munshi ◽  
Josue San Emeterio ◽  
...  
Keyword(s):  
Molecular Mechanism ◽  
Small Molecule ◽  
Ribosomal Frameshift ◽  
Short Term ◽  
X Ray ◽  
Functional Conservation ◽  
Lead Compounds ◽  
X Ray Scattering ◽  
The World ◽  
Functional Analyses

Abstract17 years after the SARS-CoV epidemic, the world is facing the COVID-19 pandemic. COVID-19 is caused by a coronavirus named SARS-CoV-2. Given the most optimistic projections estimating that it will take over a year to develop a vaccine, the best short-term strategy may lie in identifying virus-specific targets for small molecule interventions. All coronaviruses utilize a molecular mechanism called −1 PRF to control the relative expression of their proteins. Prior analyses of SARS-CoV revealed that it employs a structurally unique three-stemmed mRNA pseudoknot to stimulate high rates of −1 PRF, and that it also harbors a −1 PRF attenuation element. Altering −1 PRF activity negatively impacts virus replication, suggesting that this molecular mechanism may be therapeutically targeted. Here we present a comparative analysis of the original SARS-CoV and SARS-CoV-2 frameshift signals. Structural and functional analyses revealed that both elements promote similar rates of −1 PRF and that silent coding mutations in the slippery sites and in all three stems of the pseudoknot strongly ablated −1 PRF activity. The upstream attenuator hairpin activity has also been functionally retained. Small-angle x-ray scattering indicated that the pseudoknots in SARS-CoV and SARS-CoV-2 had the same conformation. Finally, a small molecule previously shown to bind the SARS-CoV pseudoknot and inhibit −1 PRF was similarly effective against −1 PRF in SARS-CoV-2, suggesting that such frameshift inhibitors may provide promising lead compounds to counter the current pandemic.

scholarly journals Synthesis of pentasubstituted 2-aryl pyrroles from boryl and stannyl alkynes via one-pot sequential Ti-catalyzed [2 + 2 + 1] pyrrole synthesis/cross coupling reactions

2020 ◽  
Vol 11 (37) ◽  
pp. 10236-10242
Author(s):  
Yukun Cheng ◽  
Channing K. Klein ◽  
Ian A. Tonks
Keyword(s):  
Small Molecule ◽  
Cross Coupling ◽  
Coupling Reactions ◽  
One Pot ◽  
Cross Coupling Reactions

Multisubstituted pyrroles are commonly found in many bioactive small molecule scaffolds, yet the synthesis of highly-substituted pyrrole cores remains challenging.

scholarly journals Effect of doxycycline concentrations in chicken tissues as a consequence of permanent exposure to enrofloxacin traces in drinking water

2016 ◽  
Vol 60 (3) ◽  
pp. 293-299 ◽  
Author(s):  
Małgorzata Gbylik-Sikorska ◽  
Andrzej Posyniak ◽  
Tomasz Śniegocki ◽  
Bartosz Sell ◽  
Anna Gajda ◽  
...  
Keyword(s):  
Antibacterial Agents ◽  
Animal Origin ◽  
Water Supply Systems ◽  
Antibiotic Residues ◽  
Withdrawal Time ◽  
Antibacterial Compounds ◽  
Chicken Tissues ◽  
Food Of Animal Origin ◽  
Supply Systems ◽  
Poultry Farming

AbstractIntroduction: The main problem in poultry farming is the difficulty in producing food of animal origin without using antibacterial agents. Because most antibacterial compounds are dispensed in water, some water supply systems can be contaminated by antibiotics which are then administered to the animals unintentionally. This can lead to unexpected increases in antibiotic residues in food of animal origin. The aim of the present study was to determine whether the constant exposure of chicken broilers to enrofloxacin affects the withdrawal time of a therapeutic doxycycline that is intentionally administered to the chickens.Material and Methods: The concentrations of doxycycline, enrofloxacin, and ciprofloxacin were determined by LC-MS/MS in muscles and liver of the chickens.Results: Doxycycline residue concentrations in the chicken tissues from the group that received trace amounts of enrofloxacin were nearly 50% greater than those of the group that received only doxycycline.Conclusion: These results indicated that constant exposure to enrofloxacin in trace amounts significantly influences the residual doxycycline concentration in chicken tissues.

scholarly journals Origins and Bioactivities of Natural Compounds Derived from Marine Ascidians and Their Symbionts

Marine Drugs ◽  
2019 ◽  
Vol 17 (12) ◽  
pp. 670 ◽  
Author(s):  
Xiaoju Dou ◽  
Bo Dong
Keyword(s):  
Natural Products ◽  
Secondary Metabolites ◽  
Bioactive Compounds ◽  
Natural Compounds ◽  
Marine Animals ◽  
Lead Compounds ◽  
Chemical Structures ◽  
Complex Interactions ◽  
Novel Structures ◽  
Important Drug

Marine ascidians are becoming important drug sources that provide abundant secondary metabolites with novel structures and high bioactivities. As one of the most chemically prolific marine animals, more than 1200 inspirational natural products, such as alkaloids, peptides, and polyketides, with intricate and novel chemical structures have been identified from ascidians. Some of them have been successfully developed as lead compounds or highly efficient drugs. Although numerous compounds that exist in ascidians have been structurally and functionally identified, their origins are not clear. Interestingly, growing evidence has shown that these natural products not only come from ascidians, but they also originate from symbiotic microbes. This review classifies the identified natural products from ascidians and the associated symbionts. Then, we discuss the diversity of ascidian symbiotic microbe communities, which synthesize diverse natural products that are beneficial for the hosts. Identification of the complex interactions between the symbiont and the host is a useful approach to discovering ways that direct the biosynthesis of novel bioactive compounds with pharmaceutical potentials.

scholarly journals Phosphonopeptides Revisited, in an Era of Increasing Antimicrobial Resistance

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1445 ◽  
Author(s):  
Emma C.L. Marrs ◽  
Linda Varadi ◽  
Alexandre F. Bedernjak ◽  
Kathryn M. Day ◽  
Mark Gray ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Resistance ◽  
Enterococcus Faecalis ◽  
Antibacterial Agents ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Peptide Mimetics ◽  
Antibacterial Resistance ◽  
Bacterial Isolates ◽  
New Agents ◽  
Antibacterial Compounds

Given the increase in resistance to antibacterial agents, there is an urgent need for the development of new agents with novel modes of action. As an interim solution, it is also prudent to reinvestigate old or abandoned antibacterial compounds to assess their efficacy in the context of widespread resistance to conventional agents. In the 1970s, much work was performed on the development of peptide mimetics, exemplified by the phosphonopeptide, alafosfalin. We investigated the activity of alafosfalin, di-alanyl fosfalin and β-chloro-L-alanyl-β-chloro-L-alanine against 297 bacterial isolates, including carbapenemase-producing Enterobacterales (CPE) (n = 128), methicillin-resistant Staphylococcus aureus (MRSA) (n = 37) and glycopeptide-resistant enterococci (GRE) (n = 43). The interaction of alafosfalin with meropenem was also examined against 20 isolates of CPE. The MIC50 and MIC90 of alafosfalin for CPE were 1 mg/L and 4 mg/L, respectively and alafosfalin acted synergistically when combined with meropenem against 16 of 20 isolates of CPE. Di-alanyl fosfalin showed potent activity against glycopeptide-resistant isolates of Enterococcus faecalis (MIC90; 0.5 mg/L) and Enterococcus faecium (MIC90; 2 mg/L). Alafosfalin was only moderately active against MRSA (MIC90; 8 mg/L), whereas β-chloro-L-alanyl-β-chloro-L-alanine was slightly more active (MIC90; 4 mg/L). This study shows that phosphonopeptides, including alafosfalin, may have a therapeutic role to play in an era of increasing antibacterial resistance.

scholarly journals Antibacterial Alkaloids from Chelidonium Majus Linn (Papaveraceae) Against Clinical Isolates of Methicillin-Resistant Staphylococcus Aureus

2009 ◽  
Vol 11 (4) ◽  
pp. 90 ◽  
Author(s):  
Guo Ying Zuo ◽  
Fan Yan Meng ◽  
Xiao Yan Hao ◽  
Yun Ling Zhang ◽  
Gen Chun Wang ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antibacterial Agents ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Antibacterial Effect ◽  
Dilution Method ◽  
Chelidonium Majus ◽  
Methicillin Resistant ◽  
Aerial Parts ◽  
Bioassay Guided Fractionation ◽  
Mrsa Strains

Purpose. This study describes the antibacterial effect of extracts and compounds isolated from the aerial part of Chelidonium majus Linn. (Papaveraceae) acting against clinical strains of methicillin-resistant Staphylococcus aureus (MRSA). Methods. The activities were evaluated by using the macrobroth dilution method and reported as the MICs/MBCs. Results. Bioassay-guided fractionation of the most active extract from the aerial parts (EtOAc) led to the isolation of benzo[c]phenanthridine-type alkaloids 8-hydroxydihydrosanguinarine (hhS), 8-hydroxydihydrochelerythrine (hhC), which were potently active against MRSA strains. Conclusions. The selective antibacterial activity reported in this paper for 8-hydroxylated benzo[c]phenanthridine-type alkaloids isolated from C.majus opens the possibility that they could be helpful for the developing of new antibacterial agents for treating the infection of MRSA which has created nosocomial problem worldwide.

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