scholarly journals Substituted-Amidine Functionalized Monocyclic β-Lactams: Synthesis and In Vitro Antibacterial Profile

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Lili He ◽  
Lijuan Zhai ◽  
Jian Sun ◽  
Jingwen Ji ◽  
Jinbo Ji ◽  
...  
Keyword(s):  
Antibacterial Activities ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Antibacterial Efficacy ◽  
Clinical Use ◽  
Bacterial Strains ◽  
Antibiotic Drug ◽  
Clinical Interest ◽  
Derivatives Of

Background. Owing to the intrinsic stability against common β-lactamases and metallo-lactamases, monobactams gathered special attention in antibiotic drug development. However, so far, aztreonam is the only monobactam approved by FDA for clinical use. We designed new derivatives of aztreonam to enhance its antibacterial efficacy. Methods. We synthesized a series of monocyclic β-lactams by modifying mainly at the C3 position of azetidinone ring. NH2 group at C3 of azetidinone was attached to thiazole and thiadiazole which in turn was linked to nitrogenous heterocyclic rings via amidine moieties. We then investigated the in vitro antibacterial activities of synthesized compounds against ten bacterial strains of clinical interest in comparison to aztreonam and ceftazidime. Results. All compounds showed improved antibacterial activities against tested strains compared to reference drugs. Compounds 14d and 14e were most potent and showed the highest potency against all bacterial strains, with MIC values ranging from 0.25 µg/mL to 8 µg/mL, as compared to aztreonam (MIC 16 µg/mL to >64 µg/mL) and ceftazidime (MIC >64 µg/mL). These compounds (14d and 14e) may be valuable lead targets against multidrug-resistant Gram-negative bacteria.

Synthesis and Antibacterial Activities of Amidine Substituted Monocyclic β-Lactams

2021 ◽  
Vol 17 ◽  
Author(s):  
Lijuan Zhai ◽  
Lili He ◽  
Yuanbai Liu ◽  
Ko Ko Myo ◽  
Zafar Iqbal ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Bacterial Species ◽  
Antimicrobial Effect ◽  
Antibacterial Activities ◽  
Lead Target ◽  
Bacterial Strains ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
Clinical Interest

Background: Mononcyclic β-lactams are regarded as the most resistant class of β-lactams against a series of β-lactamases though possess limited antibacterial activity. Aztreonam being the first clinically approved monobactam needs broad-spectrum efficacy through structural modification. Objective: We strive to synthesize a number of monocyclic β-lactams by varying the substituents at N1, C3 and C4 positions of azetidinone ring and study the antimicrobial effect on variable bacterial strains. Methods: Seven new monobactam derivatives 23a-g, containing substituted-amidine moieties linked to the azetidinone ring via thiazole linker, were synthesized through multistep synthesis. The final compounds were investigated for their in vitro antibacterial activities using broth microdilution method, against ten bacterial strains of clinical interest. The minimum inhibitory concentrations (MICs) of newly synthesized derivatives were compared with aztreonam, ceftazidime and meropenem, existing clinical antibiotics. Results: All compounds 23a-g showed higher antibacterial activities (MIC 0.25 µg/mL to 64 µg/mL) against tested strains as compared to aztreonam (MIC 16 µg/mL to >64 µg/mL) and ceftazidime (MIC >64 µg/mL). However all compounds, except 23d, exhibited lower antibacterial activity against all tested bacterial strains as compared to meropenem. Conclusion: Compound 23d showed comparable or improved antibacterial activity (MIC 0.25 µg/mL to 2 µg/mL) to meropenem (MIC 1 µg/mL to 2 µg/mL) in case of seven bacterial species. Therefore, compound 23d may be valuable lead target for further investigations against multi-drug resistant Gram-negative bacteria.

scholarly journals Antibacterial activity of cobalt(II) complexes with some benzimidazole derivatives

2008 ◽  
Vol 73 (12) ◽  
pp. 1153-1160 ◽  
Author(s):  
S.O. Podunavac-Kuzmanovic ◽  
V.M. Leovac ◽  
D.D. Cvetkovic
Keyword(s):  
Antibacterial Activity ◽  
Chemical Structure ◽  
Antibacterial Activities ◽  
Benzimidazole Derivatives ◽  
Wall Structure ◽  
Gram Negative Bacteria ◽  
Bacterial Strains ◽  
Gram Positive ◽  
Gram Negative

The antibacterial activities of cobalt(II) complexes with two series of benzimidazoles were evaluated in vitro against three Gram-positive bacterial strains (Bacillus cereus, Staphylococcus aureus, and Sarcina lutea) and one Gram-negative isolate (Pseudomonas aeruginosa). The minimum inhibitory concentration was determined for all the complexes. The majority of the investtigated complexes displayed in vitro inhibitory activity against very persistent bacteria. They were found to be more active against Gram-positive than Gram-negative bacteria. It may be concluded that the antibacterial activity of the compounds is related to the cell wall structure of the tested bacteria. Comparing the inhibitory activities of the tested complexes, it was found that the 1-substituted- -2-aminobenzimidazole derivatives were more active than complexes of 1-substituted- 2-amino-5,6-dimethylbenzimidazoles. The effect of chemical structure on the antibacterial activity is discussed.

Design, synthesis, and antibacterial activity of novel 8-methoxyquinoline-2-carboxamide compounds containing 1,3,4-thiadiazole moiety

2018 ◽  
Vol 73 (3-4) ◽  
pp. 117-122 ◽  
Author(s):  
Tengfei Qu ◽  
Lailiang Qu ◽  
Xiaoguang Wang ◽  
Ting Xu ◽  
Xiao Xiao ◽  
...  
Keyword(s):  
Antibacterial Activities ◽  
Combination Method ◽  
Gram Negative Bacteria ◽  
Antibacterial Efficacy ◽  
Design Synthesis ◽  
Reference Drug ◽  
Gram Positive Bacteria ◽  
Structure Activity ◽  
Antibacterial Assay

AbstractA series of novel 8-methoxyquinoline-2-carboxamide compounds containing 1,3,4-thiadiazole moiety was designed and synthesized by using an active substructure combination method. Then, the antibacterial activities of all the target compounds were evaluated in vitro against three Gram-positive bacteria and three Gram-negative bacteria. The antibacterial assay showed that some target compounds displayed moderate to good antibacterial efficacy in comparison with the reference drug Chloromycin. Some interesting results of structure-activity relationships were also discussed.

scholarly journals Infection Responsive Smart Delivery of Antibiotics Using Recombinant Spider Silk Nanospheres

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1358
Author(s):  
Pranothi Mulinti ◽  
Jacob Shreffler ◽  
Raquib Hasan ◽  
Michael Dea ◽  
Amanda E. Brooks
Keyword(s):  
Drug Delivery ◽  
Drug Release ◽  
Spider Silk ◽  
Popular Science ◽  
Multidrug Resistant ◽  
Resistance Mechanisms ◽  
Bacterial Strains ◽  
Antibiotic Drug

Frequent and inappropriate usage of antibiotics has changed the natural evolution of bacteria by reducing susceptibility and increasing resistance towards antibacterial agents. New resistance mechanisms evolved in the response to host defenses and pharmaceutical interventions are threatening our ability to treat common infections, resulting in increased mortality. In the face of this rising epidemic, antibiotic drug discovery, which has long been overlooked by big pharma, is reaching a critical low. Thus, the development of an infection-responsive drug delivery system, which may mitigate multidrug resistance and preserve the lifetime of our current antibiotic arsenal, has garnered the attention of both popular science and funding agencies. The present work describes the development of a thrombin-sensitive linker embedded into a recombinant spider silk copolymer to create a nanosphere drug delivery vehicle. Recent studies have suggested that there is an increase in thrombin-like activity during Staphylococcus aureus infection; thus, drug release from this new “smart” nanosphere can be triggered in the presence of infection. A thrombin sensitive peptide (TSP) was synthesized, and the thrombin cleavage sensitivity was determined by HPLC. The results showed no cleavage of the peptide when exposed to human serum whereas the peptide was cleaved when incubated with S. aureus exudate. Subsequently, the peptide was coupled with a silk copolymer via EDC-NHS chemistry and formulated into nanospheres encapsulating antibiotic vancomycin. These nanospheres were evaluated for in vitro infection-responsive drug release and antimicrobial activity. Finally, the drug responsive nanospheres were assessed for efficacy in an in vivo septic arthritis model. Our study provides evidence that the protein conjugate was enzyme responsive and can be used to formulate targeted drug release to combat infections against multidrug-resistant bacterial strains.

scholarly journals Benzenesulfonylation of Methyl α-D-Glucopyranoside: Synthesis, Characterization and Antibacterial Screening

2016 ◽  
Vol 64 ◽  
pp. 95-105 ◽  
Author(s):  
Sarkar M.A. Kawsar ◽  
Samia S.B.S. Nishat ◽  
Mohammad A. Manchur ◽  
Yasuhiro Ozeki
Keyword(s):  
Evaluation Studies ◽  
Antibacterial Activities ◽  
Bacterial Strains ◽  
H Nmr ◽  
Antibacterial Screening ◽  
Direct Acylation ◽  
Derivatives Of ◽  
Molecular Framework ◽  
Acyl Derivatives

A novel series of benzenesulfonyl derivatives of methyl α-D-glucopyranoside (1) were synthesized by reacting benzenesulfonyl chloride in pyridine followed by direct acylation method to yield 6-O-benzenesulfonyl derivative (2). In order to obtain newer products for antibacterial evaluation studies, the 6-O-benzenesulfonyl derivative was further transformed to a series of 2,3,4-tri-O-acyl derivatives (3-11) containing a wide variety of functionalities in a single molecular framework. All the synthesized compounds have been confirmed by IR,1H NMR and elemental analysis. These newly synthesized compounds were screened forin vitroantibacterial activity against some human pathogenic bacterial strains. The study revealed that the acylated products exhibit moderate to good antibacterial activities. It was interesting to observe that the selected compounds were more sensitive against Gram-Ve bacteria than that of the Gram-+Ve bacterial strains.

scholarly journals An in vitro Antibacterial Study of Savory Essential Oil and Geraniol in Combination with Standard Antimicrobials

2014 ◽  
Vol 9 (11) ◽  
pp. 1934578X1400901 ◽  
Author(s):  
Dragoljub L. Miladinović ◽  
Budimir S. Ilić ◽  
Branislava D. Kocić ◽  
Marija D. Miladinović
Keyword(s):  
Antibacterial Activity ◽  
Essential Oil ◽  
Antibacterial Activities ◽  
Gram Negative Bacteria ◽  
Bacterial Strains ◽  
Antibacterial Study ◽  
Synergistic Interactions ◽  
In Vitro Antibacterial Activity ◽  
Checkerboard Assay

The chemical composition and antibacterial activity of Satureja kitaibelii Wierzb. ex Heuff. (savory) essential oil were examined, as well as the association between it and standard antimicrobials: tetracycline and chloramphenicol. The antibacterial activities of geraniol, the main constituent of S. kitaibelii oil, individually and in combination with standard antimicrobials were also determined. The interactions of the essential oil and geraniol with antimicrobials toward five selected strains were evaluated using the microdilution checkerboard assay in combination with chemometric methods. Oxygenated monoterpenes were the most abundant compound class in the oil (59.7%), with geraniol (50.4%) as the major compound. The essential oil exhibited in vitro antibacterial activity against all tested bacterial strains, but the activities were lower than those of the standard antimicrobials. The combinations savory oil-chloramphenicol, savory oil-tetracycline and geraniol-chloramphenicol produced predominantly synergistic interactions (FIC indices in the range 0.21–0.87) and substantial reductions in the MIC values of antimicrobials against Gram-negative bacteria, the pharmacological treatment of which is very difficult nowadays. In the PCA and HCA analyses these combinations form a separate group.

scholarly journals Biologically relevant surrogates of coumarins: 2-phenyl H-isophosphinoline 2-oxides with antibacterial activity

2021 ◽  
Vol 16 (2) ◽  
pp. 283-296
Author(s):  
Mina Hariri ◽  
Fatemeh Darvish ◽  
Karen-Pacelye Mengue Me Ndong ◽  
Rachida Babouri ◽  
Rachida Babouri ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Antibacterial Activities ◽  
Gram Negative Bacteria ◽  
Bacterial Strains ◽  
Biologically Relevant ◽  
Gram Positive Bacteria ◽  
Disk Diffusion Assay ◽  
Selective Antimicrobial Activity ◽  
Diffusion Assay

The present study aims to investigate the in vitro antibacterial activities of several isophosphinoline-2-oxides that can be perceived as combined bio isosteres of coumarins and flavonoids. More specifically, antibacterial activity was evaluated against four bacterial strains, including the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa and the Gram-positive bacteria Staphylococcus aureus and Enterococcus faecalis by using disk diffusion assay. Notably, isophosphinoline-2-oxide compounds showed promising and highly selective antimicrobial activity against S. aureus.

scholarly journals Dioctanoyl Ultrashort Tetrabasic β-Peptides Sensitize Multidrug-Resistant Gram-Negative Bacteria to Novobiocin and Rifampicin

2021 ◽  
Vol 12 ◽  
Author(s):  
Danyel Ramirez ◽  
Liam Berry ◽  
Ronald Domalaon ◽  
Yanqi Li ◽  
Gilbert Arthur ◽  
...  
Keyword(s):  
Amino Acid ◽  
Inhibitory Concentration ◽  
Multidrug Resistant ◽  
Fatty Acyl ◽  
Gram Negative Bacteria ◽  
Wild Type ◽  
Gram Negative ◽  
Proteolytic Stability ◽  
Derivatives Of

Recently reported peptidomimetics with increased resistance to trypsin were shown to sensitize priority multidrug-resistant (MDR) Gram-negative bacteria to novobiocin and rifampicin. To further optimize proteolytic stability, β-amino acid-containing derivatives of these compounds were prepared, resulting in three dioctanoyl ultrashort tetrabasic β-peptides (dUSTBβPs). The nonhemolytic dUSTBβP 3, comprised of three β3-homoarginine residues and two fatty acyl tails eight carbons long, enhanced the antibacterial activity of various antibiotics from different classes. Notably, compound 3 retained the ability to potentiate novobiocin and rifampicin in wild-type Gram-negative bacteria against MDR clinical isolates of Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae. dUSTBβP 3 reduced the minimum inhibitory concentration of novobiocin and rifampicin below their interpretative susceptibility breakpoints. Furthermore, compound 3 exhibited improved in vitro stability (86.8 ± 3.7% remaining) relative to its α-amino acid-based counterpart (39.5 ± 7.4% remaining) after a 2 h incubation in human plasma.

scholarly journals Variation in Potency and Spectrum of Tigecycline Activity against Bacterial Strains from U.S. Medical Centers since Its Approval for Clinical Use (2006 to 2012)

2014 ◽  
Vol 58 (4) ◽  
pp. 2274-2280 ◽  
Author(s):  
Helio S. Sader ◽  
David J. Farrell ◽  
Robert K. Flamm ◽  
Ronald N. Jones
Keyword(s):  
The United States ◽  
Multidrug Resistant ◽  
Surveillance Program ◽  
Clinical Use ◽  
Bacterial Strains ◽  
Gram Positive ◽  
Content Type ◽  
Highly Active ◽  
Medical Centers

ABSTRACTTigecycline was initially approved by the U.S. Food and Drug Administration (FDA) in June 2005. We assessed the evolution of tigecyclinein vitroactivities since the initial approval of tigecycline for clinical use by analyzing the results of 7 years (2006 to 2012) of data from the SENTRY Antimicrobial Surveillance Program in the United States. We also analyzed trends over time for key resistance phenotypes. The analyses included 68,608 unique clinical isolates collected from 29 medical centers and tested for susceptibility using reference broth microdilution methods. Tigecycline was highly active against Gram-positive organisms, with MIC50and MIC90values of 0.12 and 0.25 μg/ml forStaphylococcus aureus(28,278 strains; >99.9% susceptible), 0.06 to 0.12 and 0.12 to 0.25 μg/ml for enterococci (99.3 to 99.6% susceptible), and ≤0.03 and ≤0.03 to 0.06 μg/ml for streptococci (99.9 to 100.0% susceptible), respectively. When tested against 20,457Enterobacteriaceaestrains, tigecycline MIC50and MIC90values were 0.25 and 1 μg/ml, respectively (98.3% susceptible using U.S. FDA breakpoints). No trend toward increasing tigecycline resistance (nonsusceptibility) was observed for any species or group during the study period. The prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR)Enterobacteriaceaeincreased from 4.4 and 0.5%, in 2006 to 8.5 and 1.5% in 2012, respectively. During the same period, the prevalence ofEscherichia coliandKlebsiellaspp. with an extended-spectrum β-lactamase (ESBL) phenotype increased from 5.8 and 9.1% to 11.1 and 20.4%, respectively, whereas rates of meropenem-nonsusceptibleKlebsiella pneumoniaeescalated from 2.2% in 2006 to 10.8% in 2012. The results of this investigation show that tigecycline generally retained potent activities against clinically important organisms isolated in U.S. institutions, including MDR organism subsets of Gram-positive and Gram-negative pathogens.

scholarly journals 1564. Activity of bacteriophage against multidrug resistant Klebsiella pneumoniae

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S782-S782
Author(s):  
Sailaja Puttagunta ◽  
Maya Kahan-Haanum ◽  
Sharon Kredo-Russo ◽  
Eyal Weinstock ◽  
Efrat Khabra ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Unmet Need ◽  
Multidrug Resistant ◽  
Beta Lactamase ◽  
Bacterial Strains ◽  
Antibiotic Resistant ◽  
Extended Spectrum Beta Lactamase ◽  
Novel Approach ◽  
Infection Types

Abstract Background The prevalence of extended-spectrum beta-lactamase (ESBL) producing and carbapenem resistant (CR) Klebsiella pneumoniae (KP) has significantly risen in all geographic regions. Infections due to these bacteria are associated with high mortality across different infection types. Even with newer options, there remains an unmet need for safe and effective therapeutic options to treat infections caused by ESBL and CR KP. Phage therapy offers a novel approach with an unprecedented and orthogonal mechanism of action for treatment of diseases caused by pathogenic bacterial strains that are insufficiently addressed by available antibiotics. Phage-based therapies confer a high strain-level specificity and have a strong intrinsic safety profile. Here we describe the identification of novel phages that can effectively target antibiotic resistant KP strains. Host range of the 21 phages on 33 strain KP panel via solid culture infectivity assays. Red marks resistance to infection while sensitivity to phage is marked in green Methods KP clinical strains were isolated from human stool specimens preserved in glycerol. Selective culturing was carried, followed by testing of individual colonies for motility, indole and urease production, sequenced and analyzed by Kleborate tool to determine antibiotic resistant genes. Natural phages were isolated from plaques that developed on susceptible bacterial targets, sequenced and characterized. Results Antibiotic-resistant KP strains encoding beta lactamase genes or a carbapenemase (n=33) were isolated from healthy individuals (n=3), and patients with inflammatory bowel disease (n=26) or primary sclerosing cholangitis (n=3). Isolates sequencing revealed bla CTX-M15 and/or bla SHV encoding strains and carbapenamase KPC-2. A panel of 21 phages targeting the beta-lactamase- and carbapenemase-producing KP strains were identified. Phage sequencing revealed that all phages belong to the Caudovirales order and include 6 Siphoviridae, 14 Myoviridae, and 1 Podoviridae. In vitro lytic activity of the phages was tested on the isolated bacteria and revealed a coverage of 70% of the 33 isolated antibiotic resistant strains, >50% of which were targeted by multiple phages. Conclusion Collectively, these results demonstrate the feasibility of identifying phage with potent activity against antibiotic resistant KP strains, and may provide a novel therapeutic approach for treatment of ESBL and CR KP infections. Disclosures All Authors: No reported disclosures

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