Novel pyrazoles as potent growth inhibitors of staphylococci, enterococci and Acinetobacter baumannii bacteria

2021 ◽  
Author(s):  
Ibrahim Alkhaibari ◽  
Hansa Raj KC ◽  
Duminduni H Angappulige ◽  
David Gilmore ◽  
Mohammad A Alam
Keyword(s):  
Acinetobacter Baumannii ◽  
Antimicrobial Agents ◽  
Flow Cytometry Analysis ◽  
Antibiotic Resistant ◽  
Planktonic Bacteria ◽  
New Antibiotics ◽  
Vancomycin Resistant ◽  
Potent Growth ◽  
Uptake Studies ◽  
Time Kill

Background: Methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci and Acinetobacter baumannii cause serious antibiotic-resistant infections. Finding new antibiotics to treat these infections is imperative for combating this worldwide menace. Methods & Results: In this study, the authors designed and synthesized potent antimicrobial agents using 4-trifluoromethylphenyl-substituted pyrazole derivatives. In addition to their potency against planktonic bacteria, potent compounds effectively eradicated S. aureus and Enterococcus faecalis biofilms. Human cells tolerated these compounds with good selectivity factors. Furthermore, the authors provide evidence for the mode of action of compounds based on time-kill kinetics, flow cytometry analysis of propidium iodide-treated bacteria and oxygen uptake studies. Conclusion: This study demonstrated 20 novel compounds with potent antibacterial activity that are tolerated by human cell lines.

scholarly journals Thinking Outside the Bug: Molecular Targets and Strategies to Overcome Antibiotic Resistance

2019 ◽  
Vol 20 (6) ◽  
pp. 1255 ◽  
Author(s):  
Ana Monserrat-Martinez ◽  
Yann Gambin ◽  
Emma Sierecki
Keyword(s):  
Antibiotic Resistance ◽  
Bacterial Infections ◽  
Rational Design ◽  
Disease Onset ◽  
Resistant Bacteria ◽  
Antibiotic Resistant ◽  
New Antibiotics ◽  
Resistant Strains ◽  
Vancomycin Resistant ◽  
Antibiotic Discovery

Since their discovery in the early 20th century, antibiotics have been used as the primary weapon against bacterial infections. Due to their prophylactic effect, they are also used as part of the cocktail of drugs given to treat complex diseases such as cancer or during surgery, in order to prevent infection. This has resulted in a decrease of mortality from infectious diseases and an increase in life expectancy in the last 100 years. However, as a consequence of administering antibiotics broadly to the population and sometimes misusing them, antibiotic-resistant bacteria have appeared. The emergence of resistant strains is a global health threat to humanity. Highly-resistant bacteria like Staphylococcus aureus (methicillin-resistant) or Enterococcus faecium (vancomycin-resistant) have led to complications in intensive care units, increasing medical costs and putting patient lives at risk. The appearance of these resistant strains together with the difficulty in finding new antimicrobials has alarmed the scientific community. Most of the strategies currently employed to develop new antibiotics point towards novel approaches for drug design based on prodrugs or rational design of new molecules. However, targeting crucial bacterial processes by these means will keep creating evolutionary pressure towards drug resistance. In this review, we discuss antibiotic resistance and new options for antibiotic discovery, focusing in particular on new alternatives aiming to disarm the bacteria or empower the host to avoid disease onset.

scholarly journals Syntheses and Antibiotic Evaluation of 2-{[(2R,4R)-4-Carboxy-2-hydroxypyrrolidin-1-yl]carbonyl}benzene-1,5-dicarboxylic Acids and 2-Carbamoylbenzene-1,5-dicarboxylic Acid Analogues

2016 ◽  
Vol 2016 ◽  
pp. 1-8
Author(s):  
Abdulrazaq Tukur ◽  
Isaac Asusheyi Bello ◽  
Neil Anthony Koorbanally ◽  
James Dama Habila
Keyword(s):  
Antimicrobial Activity ◽  
Dicarboxylic Acid ◽  
Nucleophilic Addition ◽  
Antimicrobial Agents ◽  
Dicarboxylic Acids ◽  
Biological Evaluation ◽  
Zone Of Inhibition ◽  
Inhibition Concentration ◽  
New Antibiotics ◽  
Vancomycin Resistant

Our search for new antibiotics led to the syntheses and biological evaluation of new classes of dicarboxylic acid analogues. The syntheses involve nucleophilic addition of different substituted benzylamine, aniline, alkylamine, and 4-hydroxyl-L-proline with carbamoylbenzoic acid. The results of the antimicrobial activity as indicated by the zone of inhibition (ZOI) showed that Z10 is the most active against Pseudomonas aeruginosa (32 mm) and least active against Candida stellatoidea (27 mm) and Vancomycin Resistant Enterococci (VRE) (27 mm), while Z7 shows the least zone of inhibition (22 mm) against Methicillin Resistant Staphylococcus aureus (MRSA). The minimum inhibition concentration (MIC) determination reveals that Z10 inhibits the growth of tested microbes at a low concentration of 6.25 μg/mL, while Z9 and Z12 inhibits the growth of most microbes at a concentration of 12.5 μg/mL, recording the least MIC. The Minimum Bactericidal/Fungicidal Concentration (MBC/MFC) results revealed that Z10 has the highest bactericidal/fungicidal effect on the test microbes, at a concentration of 12.5 μg/mL, with the exception of Candida stellatoidea and Vancomycin Resistant Enterococci (VRE) with MBC/MFC of 25 μg/mL. The result of this investigation reveals the potential of the target compounds (Z1–3,5,7–12) in the search for new antimicrobial agents.

scholarly journals In VitroActivity of Retapamulin against Staphylococcus aureus Resistant to Various Antimicrobial Agents

2013 ◽  
Vol 57 (9) ◽  
pp. 4547-4550 ◽  
Author(s):  
Louis D. Saravolatz ◽  
Joan Pawlak ◽  
Stephanie N. Saravolatz ◽  
Leonard B. Johnson
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Agents ◽  
Good Activity ◽  
Methicillin Resistant ◽  
Content Type ◽  
Vancomycin Resistant ◽  
Time Kill

ABSTRACTRetapamulin and six other antimicrobial agents were evaluated against 155 methicillin-resistantStaphylococcus aureus(MRSA) isolates, including strains resistant to vancomycin, linezolid, daptomycin, and mupirocin by microdilution tests. Time-kill assays were performed against representative MRSA, vancomycin-intermediateS. aureus(VISA), and vancomycin-resistantS. aureus(VRSA) isolates. Retapamulin and mupirocin demonstrated MIC90s of 0.12 μg/ml and 8 μg/ml, respectively, with resistance seen in 2.6% and 10% of isolates, respectively. Retapamulin maintained good activity against 94% (15/16) of mupirocin-resistant isolates.

scholarly journals Assessment by Time-Kill Methodology of the Synergistic Effects of Oritavancin in Combination with Other Antimicrobial Agents against Staphylococcus aureus

2008 ◽  
Vol 52 (10) ◽  
pp. 3820-3822 ◽  
Author(s):  
Adam Belley ◽  
Eve Neesham-Grenon ◽  
Francis F. Arhin ◽  
Geoffrey A. McKay ◽  
Thomas R. Parr ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Agents ◽  
Synergistic Effects ◽  
Clinical Development ◽  
Synergistic Activity ◽  
Gram Positive ◽  
Vancomycin Resistant ◽  
Time Kill

ABSTRACT Oritavancin is a semisynthetic lipoglycopeptide in clinical development for serious gram-positive infections. This study describes the synergistic activity of oritavancin in combination with gentamicin, linezolid, moxifloxacin, or rifampin in time-kill studies against methicillin-susceptible, vancomycin-intermediate, and vancomycin-resistant Staphylococcus aureus.

scholarly journals Rescued chlorhexidine activity by resveratrol against carbapenem-resistant Acinetobacter baumannii via down-regulation of AdeB efflux pump

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0243082
Author(s):  
Uthaibhorn Singkham-in ◽  
Paul G. Higgins ◽  
Dhammika Leshan Wannigama ◽  
Parichart Hongsing ◽  
Tanittha Chatsuwan
Keyword(s):  
Acinetobacter Baumannii ◽  
Ethidium Bromide ◽  
Antimicrobial Agents ◽  
Efflux Pump ◽  
Intracellular Accumulation ◽  
Efflux Pump Inhibitor ◽  
Carbapenem Resistant ◽  
Efflux Pump Inhibition ◽  
Synergistic Mechanism ◽  
Time Kill

The aim of this study was to determine the activity and synergistic mechanisms of resveratrol in combination with chlorhexidine against carbapenem-resistant Acinetobacter baumannii clinical isolates. The activity of resveratrol plus antimicrobial agents was determined by checkerboard and time-kill assay against carbapenem-resistant A. baumannii isolated from patients at the King Chulalongkorn Memorial Hospital, Bangkok, Thailand. Overexpression of efflux pumps that mediates chlorhexidine susceptibility was characterized by the ethidium bromide accumulation assay. The effect of resveratrol on the expression of efflux pump genes (adeB, adeJ, adeG abeS, and aceI) and the two-component regulators, adeR and adeS was determined by RT-qPCR. The combination of resveratrol and chlorhexidine resulted in strong synergistic and bactericidal activity against carbapenem-resistant A. baumannii. Up-regulation of adeB and aceI was induced by chlorhexidine. However, the addition of resveratrol increased chlorhexidine susceptibility with increased intracellular accumulation of ethidium bromide in A. baumannii indicating that resveratrol acts as an efflux pump inhibitor. Expression of adeB was significantly reduced in the combination of resveratrol with chlorhexidine indicating that resveratrol inhibits the AdeB efflux pump and restores chlorhexidine effect on A. baumannii. In conclusion, reduced adeB expression in A. baumannii was mediated by resveratrol suggesting that AdeB efflux pump inhibition contributes to the synergistic mechanism of resveratrol with chlorhexidine. Our finding highlights the potential importance of resveratrol in clinical applications.

scholarly journals Synthesis and In Vitro Antibacterial Evaluation of Schiff Bases Derived FROM 2-Chloro-3-Quinolinecarboxaldehyde

2019 ◽  
Vol 7 (1) ◽  
pp. 9-15
Author(s):  
Hamid Beyzaei ◽  
Hadis Hosseini Moghadam ◽  
Ghodsieh Bagherzade ◽  
Reza Aryan ◽  
Mohammadreza Moghaddam-Manesh
Keyword(s):  
Schiff Bases ◽  
Fungal Pathogens ◽  
Pathogenic Bacteria ◽  
Structural Changes ◽  
Antimicrobial Agents ◽  
Antimicrobial Properties ◽  
Antibiotic Resistant ◽  
Heterocyclic Schiff Bases ◽  
Time Kill

Background: Design, identification, and synthesis of new antimicrobial agents along with preventive proceedings are essential to confront antibiotic-resistant pathogenic bacteria. Heterocyclic Schiff bases are biologically important compounds whose antimicrobial potentials have been proven to bacterial and fungal pathogens. Objectives: In this study, some quinoline Schiff bases were synthesized from condensation of 2-chloro3-quinolinecarboxaldehyde and aniline derivatives. Their inhibitory activities were evaluated against 6 gram-positive and 2 gram-negative bacterial pathogens. Methods: Disc diffusion, broth microdilution, and time-kill tests were applied according to the CLSI guidelines to determine IZD, MIC, and MBC values. Results: 2-Chloro-3-quinolinecarboxaldehyde Schiff bases could inhibit the growth of bacteria with IZDs of 7.5-19.8 mm, MICs of 256-2048 μg mL-1, and MBCs of 512 to ≥2048 μg mL-1. Conclusion: Moderate antibacterial effects were observed with heterocyclic Schiff bases. Complexation and structural changes can improve their antimicrobial properties.

Synergy Testing of Vancomycin-Resistant Enterococcus faecium against Quinupristin-Dalfopristin in Combination with Other Antimicrobial Agents

1999 ◽  
Vol 43 (11) ◽  
pp. 2776-2779 ◽  
Author(s):  
S. O. Matsumura ◽  
L. Louie ◽  
M. Louie ◽  
A. E. Simor
Keyword(s):  
Clinical Evaluation ◽  
Enterococcus Faecium ◽  
Antimicrobial Agents ◽  
Vitro Activity ◽  
Vancomycin Resistant Enterococcus ◽  
In Vitro Activity ◽  
Vancomycin Resistant ◽  
Time Kill ◽  
Synergy Testing

ABSTRACT Using checkerboard and time-kill assays, we evaluated the in vitro activity of quinupristin-dalfopristin (RP 59500) alone and in combination with five other antimicrobial agents against 12 clinical strains of vancomycin-resistant Enterococcus faecium(VREF). In time-kill studies, six VREF strains exhibited synergism with the combination of quinupristin-dalfopristin and doxycycline and three exhibited synergism with quinupristin-dalfopristin plus ampicillin-sulbactam. Combinations of quinupristin-dalfopristin with these and other agents warrant further clinical evaluation for the treatment of serious VREF infections.

Nosocomial Infection Caused by Antibiotic-Resistant Organisms in the Intensive-Care Unit

1996 ◽  
Vol 17 (4) ◽  
pp. 236-248 ◽  
Author(s):  
John P. Flaherty ◽  
Robert A. Weinstein
Keyword(s):  
Intensive Care Unit ◽  
Intensive Care ◽  
Antimicrobial Agents ◽  
Selective Pressure ◽  
Antibiotic Use ◽  
Antibiotic Resistant ◽  
Gram Negative ◽  
Vancomycin Resistant Enterococci ◽  
Close Proximity ◽  
Vancomycin Resistant

AbstractResistance to antimicrobial agents is an evolving process, driven by the selective pressure of heavy antibiotic use in individuals living in close proximity to others. The intensive care unit (ICU), crowded with debilitated patients who are receiving broad-spectrum antibiotics and being cared for by busy physicians, nurses, and technicians, serves as an ideal environment for the emergence of antibiotic resistance. Problem pathogens presently include multiply resistant gram-negative bacilli, methicillin-resistantStaphylococcus aureus, and the recently emerged vancomycin-resistant enterococci. The prevention of antimicrobial resistance in ICUs should focus on recognition via routine unit-based sur veillance, improved compliance with handwashing and barrier precautions, and antibiotic-use policies tailored to individual units within hospitals.

scholarly journals Activities of Vancomycin-Containing Regimens against Colistin-Resistant Acinetobacter baumannii Clinical Strains

2013 ◽  
Vol 57 (5) ◽  
pp. 2103-2108 ◽  
Author(s):  
Jessica A. O'Hara ◽  
Lauretta A. Ambe ◽  
Leila G. Casella ◽  
Bethany M. Townsend ◽  
Mark R. Pelletier ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Lipid A ◽  
Antimicrobial Agents ◽  
Galleria Mellonella ◽  
Therapeutic Benefit ◽  
Content Type ◽  
Clinical Strains ◽  
Two Component Signal Transduction ◽  
Time Kill ◽  
Unique Amino Acid

ABSTRACTTreatment of infections due to extensively drug-resistant (XDR)Acinetobacter baumanniioften involves the use of antimicrobial agents in combination. Various combinations of agents have been proposed, with colistin serving as the backbone in many of them. Recent data suggest that glycopeptides, in particular vancomycin, may have unique activity against laboratory-adapted and clinical strains ofA. baumannii, alone and in combination with colistin. The aim of the present study was to test this approach against three unique colistin-resistantA. baumanniiclinical strains using combinations of vancomycin (VAN), colistin (COL), and doripenem (DOR). All three strains possessed the signature phosphoethanolamine modification of the lipid A moiety associated with colistin resistance and unique amino acid changes in the PmrAB two-component signal transduction system not observed in colistin-susceptible strains. In checkerboard assays, synergy (defined as a fractional inhibitory concentration index [FICI] of ≤0.5) was observed between COL and VAN for all three strains tested and between COL and DOR in two strains. In time-kill assays, the combinations of COL-DOR, COL-VAN, and COL-DOR-VAN resulted in complete killing of colistin-resistantA. baumanniiin 1, 2, and all 3 strains, respectively. In theGalleria mellonellamoth model of infection, the combinations of DOR-VAN and COL-DOR-VAN led to significantly increased survival of the larvae, compared with other combinations and monotherapy. These findings suggest that regimens containing vancomycin may confer therapeutic benefit for infection due to colistin-resistantA. baumannii.

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