scholarly journals Flavonoids as Potential anti-MRSA Agents through Modulation of PBP2a: A Computational and Experimental Study

Antibiotics ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 562 ◽  
Author(s):  
Hani A. Alhadrami ◽  
Ahmed A. Hamed ◽  
Hossam M. Hassan ◽  
Lassaad Belbahri ◽  
Mostafa E. Rateb ◽  
...  
Keyword(s):  
Antimicrobial Agents ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Synergistic Effects ◽  
Binding Modes ◽  
Penicillin Binding Protein ◽  
Simulation Experiments ◽  
Life Threatening ◽  
Resistant Strains ◽  
Common Plant

Recently, the interest in plant-derived antimicrobial agents has increased. However, there are no sufficient studies dealing with their modes of action. Herein, we investigate an in-house library of common plant-based phenolic compounds for their potential antibacterial effects against the methicillin-resistant Staphylococcus aureus (MRSA), a widespread life-threatening superbug. Flavonoids, which are considered major constituents in the plant kingdom, were found to be a promising class of compounds against MRSA, particularly the non-glycosylated ones. On the other hand, the glycosylated derivatives, along with the flavonolignan silibinin A, were able to restore the inhibitory activity of ampicillin against MRSA. To explore the mode of action of this class, they were subjected to an extensive inverse virtual screening (IVS), which suggested penicillin-binding protein 2a (PBP2a) as a possible target that mediates both the antibacterial and the antibiotic-synergistic effects of this class of compounds. Further molecular docking and molecular dynamic simulation experiments were conducted to support the primary IVS and the in vitro results and to study their binding modes with PBP2a. Our findings shed a light on plant-derived natural products, notably flavonoids, as a promising and readily available source for future adjuvant antimicrobial therapy against resistant strains.

scholarly journals Comparative In Vitro Activities of AC98-6446, a Novel Semisynthetic Glycopeptide Derivative of the Natural Product Mannopeptimycin α, and Other Antimicrobial Agents against Gram-Positive Clinical Isolates

2004 ◽  
Vol 48 (3) ◽  
pp. 739-746 ◽  
Author(s):  
Peter J. Petersen ◽  
T. Z. Wang ◽  
Russell G. Dushin ◽  
Patricia A. Bradford
Keyword(s):  
Natural Product ◽  
Bactericidal Activity ◽  
Antimicrobial Agents ◽  
Marked Decrease ◽  
Gram Positive ◽  
Novel Structure ◽  
Resistant Strains ◽  
Vancomycin Resistant ◽  
Further Development

ABSTRACT AC98-6446 is a novel semisynthetic cyclic glycopeptide antibiotic related to the natural product mannopeptimycin α (AC98-1). In the present study the activity of AC98-6446 was evaluated against a variety of recent clinical gram-positive pathogens including multiply resistant strains. AC98-6446 demonstrated similar potent activities against methicillin-susceptible and methicillin-resistant staphylococci and glycopeptide-intermediate staphylococcal isolates (MICs at which 90% of isolates are inhibited [MIC90s], 0.03 to 0.06 μg/ml). AC98-6446 also demonstrated good activities against both vancomycin-resistant and -susceptible strains of enterococci (MIC90s, 0.12 and 0.25 μg/ml, respectively) as well as against streptococcal strains (MIC90s, ≤ 0.008 to 0.03 μg/ml). AC98-6446 demonstrated bactericidal activity in terms of the reduction in the viable counts (>3 log10 CFU/ml) of staphylococcal and streptococcal isolates and a marked decrease in the viable counts of most enterococcal strains (from 0.2 to 2.5 log10 CFU/ml). Unlike vancomycin, which demonstrates time-dependent killing, AC98-6446 demonstrated concentration-dependent killing. The potent activity, novel structure, and bactericidal activity demonstrated by AC98-6446 make it an attractive candidate for further development.

In vitro activity of antimicrobial agents with and without sulbactam, EDTA and sulbactam-EDTA on ESBLs-producing Escherichia coli isolated from healthy Tibetan yaks

2020 ◽  
Author(s):  
Baoguang Liu ◽  
Xiaoling Yuan ◽  
Yiheng Chen ◽  
Xiaoshen Li ◽  
Ming Bai ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Nasal Swab ◽  
Antimicrobial Agents ◽  
Synergistic Effects ◽  
E Coli ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
Third Generation Cephalosporins ◽  
Enhance Activity

Abstract Background The spread of ESBLs-producing bacteria has been strikingly rapid in many regions of the world and it causes therapeutic difficulties in everyday practice. The aims of this study were to investigate the prevalence and susceptibilities of ESBLs-producing Escherichia coli isolates from healthy Tibetan yaks in China, to evaluate the activity of drug combinations on ESBLs-producing E. coli isolates. Methods From July 2018 to August 2019, a total of 750 nasal swab samples were tested for the presence of E. coli and ESBLs-producing strains. The MICs of 11 antimicrobial agents alone and combinations with sulbactam, EDTA or sulbactam-EDTA against 240 ESBLs-producing E.coli strains were determined by the broth microdilution method. Results Overall, 59.87% (n = 449) of the samples were positive for E. coli, 240 (53.45%) of 449 E. coli isolates were confirmed to be ESBLs-producing. The addition of sulbactam to the third generation cephalosporins, amikacin and fosfomycin for all isolates resulted in low MICs, increasing the level of susceptibility from 0, 0 and 0% to 50 ~ 87.5, 4.2 and 100% respectively. The addition of EDTA to fluoroquinolones, doxycycline, florfenicol, amikacin and fosfomycin, showed improved activities and resulted in low MICs, increasing the level of susceptibility from 0, 0, 8.3, 0 and 0% to 4.2 ~ 29.2, 33.3, 33.3, 66.7 and 45.8%, respectively. All other antibacterials (except fluoroquinolones, doxycycline and florfenicol), when combined with sulbactam-EDTA, were found to be more active than combinations only with sulbactam or with EDTA against most of isolates, with lower MIC50s and MIC90s. Conclusion In conclusion, ESBLs-producing E. coli isolates were widespread in healthy Tibetan yaks in China. ESBLs-producing E. coli isolates exhibited varying degrees of multidrug resistance. This study these findings suggested that sulbactam can enhance activity of β-lactams and some non-β-lactams of antimicrobial agents and had a synergistic effects with EDTA in improving activities of some families of antimicrobials.

scholarly journals Nitrofurantoin Combined With Amikacin: A Promising Alternative Strategy for Combating MDR Uropathogenic Escherichia coli

2020 ◽  
Vol 10 ◽  
Author(s):  
Zi-Xing Zhong ◽  
Ze-Hua Cui ◽  
Xiao-Jie Li ◽  
Tian Tang ◽  
Zi-Jian Zheng ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Bacterial Resistance ◽  
Galleria Mellonella ◽  
Synergistic Effects ◽  
Promising Alternative ◽  
Poor Patient Compliance ◽  
Life Threatening ◽  
Tract Infections ◽  
Time Kill

Urinary tract infections (UTI) are common infections that can be mild to life threatening. However, increased bacterial resistance and poor patient compliance rates have limited the effectiveness of conventional antibiotic therapies. Here, we investigated the relationship between nitrofurantoin and amikacin against 12 clinical MDR uropathogenic Escherichia coli (UPEC) strains both in vitro and in an experimental Galleria mellonella model. In vitro synergistic effects were observed in all 12 test strains by standard checkerboard and time-kill assays. Importantly, amikacin or nitrofurantoin at half of the clinical doses were not effective in the treatment of UPEC infections in the G. mellonella model but the combination therapy significantly increased G. mellonella survival from infections caused by all 12 study UPEC strains. Taken together, these results demonstrated synergy effects between nitrofurantoin and amikacin against MDR UPEC.

scholarly journals Synergy of Linezolid with Several Antimicrobial Agents against Linezolid-Methicillin-Resistant Staphylococcal Strains

Antibiotics ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 496
Author(s):  
María-José Valderrama ◽  
María Alfaro ◽  
Icíar Rodríguez-Avial ◽  
Elvira Baos ◽  
Carmen Rodríguez-Avial ◽  
...  
Keyword(s):  
Antimicrobial Agents ◽  
Synergistic Effects ◽  
Ribosomal Subunit ◽  
Antagonistic Effect ◽  
Prolonged Treatment ◽  
Synergistic Activity ◽  
Methicillin Resistant ◽  
Resistant Strains ◽  
Time Kill ◽  
Selection Of

Linezolid is a synthetic oxazolydinone active against multi-resistant Gram-positive cocci that inhibits proteins synthesis by interacting with the 50S ribosomal subunit. Although linezolid-resistant strains are infrequent, several outbreaks have been recently described, associated with prolonged treatment with the antibiotic. As an alternative to monotherapy, the combination of different antibiotics is a commonly used option to prevent the selection of resistant strains. In this work, we evaluated combinations of linezolid with classic and new aminoglycosides (amikacin, gentamicin and plazomicin), carbapenems (doripenem, imipenem and meropenem) and fosfomycin on several linezolid- and methicillin-resistant strains of Staphylococcus aureus and S. epidermidis, isolated in a hospital intensive care unit in Madrid, Spain. Using checkerboard and time-kill assays, interesting synergistic effects were encountered for the combination of linezolid with imipenem in all the staphylococcal strains, and for linezolid–doripenem in S.epidermidis isolates. The combination of plazomicin seemed to also have a good synergistic or partially synergistic activity against most of the isolates. None of the combinations assayed showed an antagonistic effect.

scholarly journals In Vitro Susceptibility of Thai Pythium insidiosum Isolates to Antibacterial Agents

2020 ◽  
Vol 64 (4) ◽  
Author(s):  
Navaporn Worasilchai ◽  
Ariya Chindamporn ◽  
Rongpong Plongla ◽  
Pattama Torvorapanit ◽  
Kasama Manothummetha ◽  
...  
Keyword(s):  
Antibacterial Agents ◽  
Antifungal Agents ◽  
Radical Surgery ◽  
Synergistic Effects ◽  
In Vitro Susceptibility ◽  
Pythium Insidiosum ◽  
Content Type ◽  
Life Threatening ◽  
Report Data

ABSTRACT Human pythiosis is a life-threatening human disease caused by Pythium insidiosum. In Thailand, vascular pythiosis is the most common form and carries a mortality rate of 10 to 40%, despite aggressive treatment with radical surgery, antifungal agents, and immunotherapy. Itraconazole and terbinafine have been the mainstay of treatment, until recently, based on case report data showing potential synergistic effects against Brazilian P. insidiosum isolates. However, the synergistic effects of itraconazole and terbinafine against Thai P. insidiosum isolates were not observed. This study tested the in vitro susceptibilities of 27 Thai human P. insidiosum isolates (clade II, n = 17; clade IV, n = 10), 12 Thai environmental P. insidiosum isolates (clade II, n = 4; clade IV, n = 8), and 11 non-Thai animal P. insidiosum isolates (clade I, n = 9; clade II, n = 2) to antibiotics in eight antibacterial classes to evaluate alternative effective treatments. Tetracycline and macrolide antibiotics demonstrated in vitro activity against Thai P. insidiosum isolates, with doxycycline MICs (1 to 16 μg/ml), minocycline MICs (1 to 4 μg/ml), tigecycline MICs (1 to 4 μg/ml), azithromycin MICs (1 to 16 μg/ml), and clarithromycin MICs (0.125 to 8 μg/ml) being the lowest, on average. Synergistic effects of tetracyclines and macrolides were also observed.

scholarly journals Struggle To Survive: the Choir of Target Alteration, Hydrolyzing Enzyme, and Plasmid Expression as a Novel Aztreonam-Avibactam Resistance Mechanism

mSystems ◽  
2020 ◽  
Vol 5 (6) ◽  
Author(s):  
Ke Ma ◽  
Yu Feng ◽  
Alan McNally ◽  
Zhiyong Zong
Keyword(s):  
Antimicrobial Resistance ◽  
Antisense Rna ◽  
Antimicrobial Agents ◽  
Binding Protein ◽  
Resistance Mechanism ◽  
Resistance Mechanisms ◽  
Penicillin Binding Protein ◽  
Plasmid Copy ◽  
Copy Numbers

ABSTRACT Aztreonam-avibactam is a promising antimicrobial combination against multidrug-resistant organisms, such as carbapenemase-producing Enterobacterales. Resistance to aztreonam-avibactam has been found, but the resistance mechanism remains poorly studied. We recovered three Escherichia coli isolates of an almost identical genome but exhibiting varied aztreonam-avibactam resistance. The isolates carried a cephalosporinase gene, blaCMY-42, on IncIγ plasmids with a single-nucleotide variation in an antisense RNA-encoding gene, inc, of the replicon. The isolates also had four extra amino acids (YRIK) in penicillin-binding protein 3 (PBP3) due to a duplication of a 12-nucleotide (TATCGAATTAAC) stretch in pbp3. By cloning and plasmid-curing experiments, we found that elevated CMY-42 cephalosporinase production or amino acid insertions in PBP3 alone mediated slightly reduced susceptibility to aztreonam-avibactam, but their combination conferred aztreonam-avibactam resistance. We show that the elevated CMY-42 production results from increased plasmid copy numbers due to mutations in inc. We also verified the findings using in vitro mutation assays, in which aztreonam-avibactam-resistant mutants also had mutations in inc and elevated CMY-42 production compared with the parental strain. This choir of target modification, hydrolyzing enzyme, and plasmid expression represents a novel, coordinated, complex antimicrobial resistance mechanism and also reflects the struggle of bacteria to survive under selection pressure imposed by antimicrobial agents. IMPORTANCE Carbapenemase-producing Enterobacterales (CPE) is a serious global challenge with limited therapeutic options. Aztreonam-avibactam is a promising antimicrobial combination with activity against CPE producing serine-based carbapenemases and metallo-β-lactamases and has the potential to be a major option for combatting CPE. Aztreonam-avibactam resistance has been found, but resistance mechanisms remain largely unknown. Understanding resistance mechanisms is essential for optimizing treatment and developing alternative therapies. Here, we found that either penicillin-binding protein 3 modification or the elevated expression of cephalosporinase CMY-42 due to increased plasmid copy numbers does not confer resistance to aztreonam-avibactam, but their combination does. We demonstrate that increased plasmid copy numbers result from mutations in antisense RNA-encoding inc of the IncIγ replicon. The findings reveal that antimicrobial resistance may be due to concerted combinatorial effects of target alteration, hydrolyzing enzyme, and plasmid expression and also highlight that resistance to any antimicrobial combination will inevitably emerge.

scholarly journals Emergence of Penicillin-ResistantStreptococcus Pneumoniaein Southern Ontario, 1993–94

1995 ◽  
Vol 6 (3) ◽  
pp. 157-160 ◽  
Author(s):  
Andrew E Simor ◽  
Anita Rachlis ◽  
Lisa Louie ◽  
Janet Goodfellow ◽  
Marie Louie
Keyword(s):  
Antimicrobial Agents ◽  
Clinical Laboratory ◽  
Tertiary Care ◽  
National Committee ◽  
In Vitro Susceptibility ◽  
Southern Ontario ◽  
Recent Emergence ◽  
Resistant Strains ◽  
High Level

Objective: To determine the prevalence of resistance ofStreptococcus pneumoniaeto penicillin and other antimicrobial agents in metropolitan Toronto.Design: Consecutive pneumococcal isolates from different patients were obtained from two private community-based laboratories and from patients assessed in the emergency department of a tertiary-care teaching hospital in Toronto, Ontario between June and December 1993, and between March and October 1994. In vitro susceptibility testing was done by broth microdilution in accordance with National Committee for Clinical Laboratory Standards guidelines.Results: Twenty (7.3±3.1%) of 274 pneumococcal isolates were resistant to penicillin; six (30%) isolates had high-level resistance (minimal inhibitory concentration [mic] 2.0 μg/mL or greater); and 14 isolates had intermediate resistance (mic0.1 to 1.0 μg/mL). Penicillin-resistant strains were also frequently resistant to tetracycline (55%), cotrimoxazole (50%), erythromycin (40%) and cefuroxime (35%). Resistant strains comprised several serotypes: 19F (six isolates), 9V (three), 23F (three), and one each of 6A, 6B, 14, and 19A; four isolates were nontypeable.Conclusions: There has been a recent emergence of penicillin-resistantS pneumoniaein southern Ontario. National and regional surveillance is warranted to determine the extent of the problem elsewhere in Canada.

scholarly journals Comparative In Vitro Activities of Relebactam, Imipenem, the Combination of the Two, and Six Comparator Antimicrobial Agents against 432 Strains of Anaerobic Organisms, Including Imipenem-Resistant Strains

2017 ◽  
Vol 62 (2) ◽  
Author(s):  
Ellie J. C. Goldstein ◽  
Diane M. Citron ◽  
Kerin L. Tyrrell ◽  
Eliza Leoncio ◽  
C. Vreni Merriam
Keyword(s):  
Antimicrobial Agents ◽  
Beta Lactamase ◽  
Resistant Strains ◽  
Lactamase Inhibitor

ABSTRACT Relebactam is an important beta-lactamase inhibitor for certain aerobic organisms, but alone it has no antianaerobic activity, with most anaerobes having MICs of ≥32 μg/ml with the exception of a very few strains. There was no enhancement or antagonism of imipenem activity with the addition of relebactam, including activity against imipenem-resistant strains. The relebactam-imipenem combination had excellent overall activity against the anaerobes tested.

scholarly journals In VitroAntibacterial Activity of the Ceftazidime-Avibactam Combination against Enterobacteriaceae, Including Strains with Well-Characterized β-Lactamases

2015 ◽  
Vol 59 (4) ◽  
pp. 1931-1934 ◽  
Author(s):  
Premavathy Levasseur ◽  
Anne-Marie Girard ◽  
Christine Miossec ◽  
John Pace ◽  
Ken Coleman
Keyword(s):  
Antibacterial Activity ◽  
Antimicrobial Agents ◽  
The Novel ◽  
Content Type ◽  
Class A ◽  
Fixed Weight ◽  
Class D ◽  
Resistant Strains ◽  
Esbl Producers

ABSTRACTThe novel β-lactamase inhibitor avibactam is a potent inhibitor of class A, class C, and some class D enzymes. Thein vitroantibacterial activity of the ceftazidime-avibactam combination was determined for a collection ofEnterobacteriaceaeclinical isolates; this collection was enriched for resistant strains, including strains with characterized serine β-lactamases. The inhibitor was added either at fixed weight ratios to ceftazidime or at fixed concentrations, with the latter type of combination consistently resulting in greater potentiation of antibacterial activity. In the presence of 4 μg/ml of avibactam, the ceftazidime MIC50and MIC90(0.25 and 2 μg/ml, respectively) were both below the CLSI breakpoint for ceftazidime. Further comparisons with reference antimicrobial agents were performed using this fixed inhibitor concentration. Against most ceftazidime-susceptible and -nonsusceptible isolates, the addition of avibactam resulted in a significant increase in ceftazidime activity, with MICs generally reduced 256-fold for extended-spectrum β-lactamase (ESBL) producers, 8- to 32-fold for CTX-M producers, and >128-fold for KPC producers. Overall, MICs of a ceftazidime-avibactam combination were significantly lower than those of the comparators piperacillin-tazobactam, cefotaxime, ceftriaxone, and cefepime and similar or superior to those of imipenem.

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