scholarly journals Pharmacodynamic Functions of Synthetic Derivatives for Treatment of Methicillin-Resistant Staphylococcus aureus (MRSA) and Mycobacterium tuberculosis

2020 ◽  
Vol 11 ◽  
Author(s):  
Mojdeh Dinarvand ◽  
Malcolm P. Spain ◽  
Fatemeh Vafaee
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Activity ◽  
Mycobacterium Tuberculosis ◽  
Antimicrobial Agents ◽  
Resistant Bacteria ◽  
Synthetic Compounds ◽  
Methicillin Resistant ◽  
Chemical Structures ◽  
Time Kill

Drug resistant bacteria have emerged, so robust methods are needed to evaluate combined activities of known antibiotics as well as new synthetic compounds as novel antimicrobial agents to treatment efficacy in severe bacterial infections. Marine natural products (MNPs) have become new strong leads in the drug discovery endeavor and an effective alternative to control infections. Herein, we report the bioassay guided fractionation of marine extracts from the sponges Lendenfeldia, Ircinia, and Dysidea that led us to identify novel compounds with antimicrobial properties. Chemical synthesis of predicted compounds and their analogs has confirmed that the proposed structures may encode novel chemical structures with promising antimicrobial activity against the medically important pathogens. Several of the synthetic analogs exhibited potent and broad spectrum in vitro antibacterial activity, especially against the Methicillin-resistant Staphylococcus aureus (MRSA) (MICs to 12.5 μM), Mycobacterium tuberculosis (MICs to 0.02 μM), uropathogenic Escherichia coli (MIC o 6.2 μM), and Pseudomonas aeruginosa (MIC to 3.1 μM). Checkerboard assay (CA) and time-kill studies (TKS) experiments analyzed with the a pharmacodynamic model, have potentials for in vitro evaluation of new and existing antimicrobials. In this study, CA and TKS were used to identify the potential benefits of an antibiotic combination (i.e., synthetic compounds, vancomycin, and rifampicin) for the treatment of MRSA and M. tuberculosis infections. CA experiments indicated that the association of compounds 1a and 2a with vancomycin and compound 3 with rifampicin combination have a synergistic effect against a MRSA and M. tuberculosis infections, respectively. Furthermore, the analysis of TKS uncovered bactericidal and time-dependent properties of the synthetic compounds that may be due to variations in hydrophobicity and mechanisms of action of the molecules tested. The results of cross-referencing antimicrobial activity, and toxicity, CA, and Time-Kill experiments establish that these synthetic compounds are promising potential leads, with a favorable therapeutic index for antimicrobial drug development.

scholarly journals In vitro activities of oxazolidinone compounds U100592 and U100766 against Staphylococcus aureus and Staphylococcus epidermidis.

1996 ◽  
Vol 40 (3) ◽  
pp. 799-801 ◽  
Author(s):  
G W Kaatz ◽  
S M Seo
Keyword(s):  
Staphylococcus Aureus ◽  
Staphylococcus Epidermidis ◽  
Inhibitory Activity ◽  
Antimicrobial Agents ◽  
Methicillin Resistant ◽  
Clinical Strains ◽  
Time Kill

The new oxazolidinone antimicrobial agents U100592 and U100766 demonstrated good in vitro inhibitory activity against clinical strains of Staphylococcus aureus and Staphylococcus epidermidis regardless of methicillin susceptibility. Both agents appeared bacteriostatic by time-kill analysis. Stable resistance to low multiples of the MIC of either drug could be produced only in methicillin-resistant S. aureus.

scholarly journals Novel Chimeric Lysin with High-Level Antimicrobial Activity against Methicillin-Resistant Staphylococcus aureus In Vitro andIn Vivo

2013 ◽  
Vol 58 (1) ◽  
pp. 536-542 ◽  
Author(s):  
Hang Yang ◽  
Yun Zhang ◽  
Junping Yu ◽  
Yanling Huang ◽  
Xian-En Zhang ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Activity ◽  
Antimicrobial Agents ◽  
Catalytic Domain ◽  
Intraperitoneal Administration ◽  
Methicillin Resistant ◽  
Content Type ◽  
Cell Wall Binding

ABSTRACTThe treatment of infections caused by methicillin-resistantStaphylococcus aureus(MRSA) is a challenge worldwide. In our search for novel antimicrobial agents against MRSA, we constructed a chimeric lysin (named as ClyH) by fusing the catalytic domain of Ply187 (Pc) with the non-SH3b-like cell wall binding domain of phiNM3 lysin. Herein, the antimicrobial activity of ClyH against MRSA strainsin vitroandin vivowas studied. Our results showed that ClyH could kill all of the tested clinical isolates of MRSA with higher efficacy than lysostaphin as well as its parental enzyme. The MICs of ClyH against clinicalS. aureusstrains were found to be as low as 0.05 to 1.61 mg/liter. In a mouse model, a single intraperitoneal administration of ClyH protected mice from death caused by MRSA, without obvious harmful effects. The present data suggest that ClyH has the potential to be an alternative therapeutic agent for the treatment of infections caused by MRSA.

scholarly journals Antistaphylococcal Activity of Oritavancin and Its Synergistic Effect in Combination with Other Antimicrobial Agents

2014 ◽  
Vol 58 (10) ◽  
pp. 6251-6254 ◽  
Author(s):  
Gengrong Lin ◽  
Glenn Pankuch ◽  
Peter C. Appelbaum ◽  
Klaudia Kosowska-Shick
Keyword(s):  
Staphylococcus Aureus ◽  
Synergistic Effect ◽  
Antimicrobial Agents ◽  
Methicillin Resistant ◽  
Content Type ◽  
Antistaphylococcal Activity ◽  
Vancomycin Resistant ◽  
Time Kill

ABSTRACTOritavancin exhibitedin vitroactivity against 169 strains of vancomycin-susceptible, methicillin-resistantStaphylococcus aureus(MRSA) with MICs ranging from 0.03 to 1 μg/ml and against vancomycin-intermediate MRSA (VISA;n= 29), heterogeneous vancomycin-intermediate MRSA (hVISA;n= 5), and vancomycin-resistant MRSA (n= 5) strains, with MICs ranging from 0.12 to 4 μg/ml. For 10 MRSA isolates comprising 5 VISA and 5 hVISA strains, synergy between oritavancin and gentamicin, linezolid, or rifampin was observed against most of the strains tested using a time-kill method.

scholarly journals In Vitro Killing of Community-Associated Methicillin-Resistant Staphylococcus aureus with Drug Combinations

2004 ◽  
Vol 48 (10) ◽  
pp. 4016-4019 ◽  
Author(s):  
Samuel A. Shelburne ◽  
Daniel M. Musher ◽  
Kristina Hulten ◽  
Heather Ceasar ◽  
Michael Y. Lu ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Drug Combinations ◽  
Methicillin Resistant ◽  
Common Drug ◽  
Time Kill ◽  
Hospital Acquired

ABSTRACT This study employs time-kill techniques to examine the most common drug combinations used in the therapy of methicillin-resistant Staphylococcus aureus (MRSA) infections, vancomycin plus either gentamicin or rifampin. Community-associated MRSA were more likely to be synergistically inhibited by combinations of vancomycin and gentamicin versus vancomycin alone compared to inhibition associated with hospital-acquired strains.

scholarly journals Novel Antibiotic Combinations of Diverse Subclasses for Effective Suppression of Extensively Drug-Resistant Methicillin-Resistant Staphylococcus aureus (MRSA)

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Shumyila Nasir ◽  
Muhammad Sufyan Vohra ◽  
Danish Gul ◽  
Umm E Swaiba ◽  
Maira Aleem ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Clavulanic Acid ◽  
Antimicrobial Agents ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Multidrug Resistant ◽  
Methicillin Resistant ◽  
Development Of Resistance ◽  
Amoxicillin Clavulanic Acid ◽  
Combination Antibiotics ◽  
Time Kill

The emergence of multidrug-resistant pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), the chief etiological agent for a range of refractory infections, has rendered all β-lactams ineffective against it. The treatment process is further complicated with the development of resistance to glycopeptides, primary antibiotics for treatment of MRSA. Antibiotic combination therapy with existing antimicrobial agents may provide an immediate treatment option. Minimum inhibitory concentrations (MICs) of 18 different commercially available antibiotics were determined along with their 90 possible pairwise combinations and 64 triple combinations to filter out 5 best combinations. Time-Kill kinetics of these combinations were then analyzed to find collateral bactericidal combinations which were then tested on other randomly selected MRSA isolates. Among the top 5 combinations including levofloxacin-ceftazidime; amoxicillin/clavulanic acid-tobramycin; amoxicillin/clavulanic acid-cephradine; amoxicillin/clavulanic acid-ofloxacin; and piperacillin/tazobactam-tobramycin, three combinations were found to be collaterally effective. Levofloxacin-ceftazidime acted synergistically in 80% of the tested clinical MRSA isolates. First-line β-lactams of lower generations can be used effectively against MRSA infection when used in combination. Antibiotics other than glycopeptides may still work in combination.

scholarly journals Polyketides from an Endophytic Aspergillus fumigatus Isolate Inhibit the Growth of Mycobacterium tuberculosis and MRSA

2015 ◽  
Vol 10 (10) ◽  
pp. 1934578X1501001 ◽  
Author(s):  
Andrew J. Flewelling ◽  
Amanda L Bishop ◽  
John A. Johnson ◽  
Christopher A. Gray
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Activity ◽  
Mycobacterium Tuberculosis ◽  
Aspergillus Fumigatus ◽  
Crude Extract ◽  
Antimycobacterial Activity ◽  
Methicillin Resistant ◽  
Bioassay Guided Fractionation ◽  
Chaetoglobosin A

The crude extract of Aspergillus fumigatus isolate AF3-093A, an endophyte of the brown algaFucus vesiculosus, showed significant antimicrobial activity in initial bioactivity screens. Bioassay-guided fractionation of the extract led to the isolation of flavipin, chaetoglobosin A and chaetoglobosin B, all of which inhibited the growth of Staphylococcus aureus, methicillin-resistant S. aureus and Mycobacterium tuberculosis H37Ra. The antimycobacterial activity of these compounds has not been previously reported.

scholarly journals Evaluation of a Bioengineered Honey and Its Synthetic Equivalent as Novel Staphylococcus aureus Biofilm-Targeted Topical Therapies in Chronic Rhinosinusitis

2019 ◽  
Vol 34 (1) ◽  
pp. 80-86 ◽  
Author(s):  
Dionyssia Papadopoulou ◽  
Alicja Dabrowska ◽  
Philip G. Harries ◽  
Jeremy S. Webb ◽  
Raymond N. Allan ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Antimicrobial Activity ◽  
Chronic Rhinosinusitis ◽  
In Vitro Study ◽  
Sinus Surgery ◽  
Bacterial Strains ◽  
Methicillin Resistant ◽  
Log Reduction ◽  
Lower Minimum Inhibitory Concentration

Background Chronic rhinosinusitis (CRS) is a common condition which affects the quality of life of millions of patients worldwide and has a significant impact on health-care resources. While Staphylococcus aureus bacterial biofilms play an important role in this disease, antimicrobial therapy is rarely effective and may promote antibiotic resistance. Thus, development of novel biofilm-targeting and antibiotic-sparing therapies is highly desirable and urgently required. Objective This in vitro study evaluated the antimicrobial activity of a novel synthetic honey-equivalent product which was designed to have the same reactive oxygen release profile as the engineered honey SurgihoneyRO™. Methods Treatment efficacy was investigated by assessment of planktonic growth, biofilm viability, thickness, and biomass using 12 CRS-related S. aureus mucosal bacterial strains. Results Both SurgihoneyRO™ and the synthetic honey-equivalent product inhibited growth of planktonic methicillin-resistant and methicillin-sensitive S. aureus strains, with the synthetic honey-equivalent product exhibiting a lower minimum inhibitory concentration. Treatment of established S. aureus biofilms reduced biofilm viability with 24-hour treatment resulting in a 2-log reduction in viability of biofilms formed by methicillin-resistant strains and a 1-log reduction in biofilms formed by methicillin-sensitive strains. Conclusions This preliminary study shows that the synthetic honey-equivalent product provides marked antimicrobial activity against S. aureus biofilms, with the potential for development in the clinical setting as an adjunctive biofilm-targeted therapy in CRS. The ultimate aim of such a product would be to reduce the need for antibiotics, steroids, and invasive surgical procedures in CRS patients as well as improving clinical outcomes following endoscopic sinus surgery.

scholarly journals Ceftobiprole EfficacyIn Vitroagainst Panton-Valentine Leukocidin Production andIn Vivoagainst Community-Associated Methicillin-Resistant Staphylococcus aureus Osteomyelitis in Rabbits

2012 ◽  
Vol 56 (12) ◽  
pp. 6291-6297 ◽  
Author(s):  
Azzam Saleh-Mghir ◽  
Oana Dumitrescu ◽  
Aurélien Dinh ◽  
Yassine Boutrad ◽  
Laurent Massias ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Methicillin Resistant ◽  
Content Type ◽  
The Mean ◽  
Mrsa Strains ◽  
Time Kill ◽  
Panton Valentine Leukocidin ◽  
Valentine Leukocidin

ABSTRACTCommunity-associated methicillin-resistantStaphylococcus aureus(CA-MRSA) can cause osteomyelitis with severe sepsis and/or local complications in which a Panton-Valentine leukocidin (PVL) role is suspected.In vitrosub-MIC antibiotic effects on growth and PVL production by 11 PVL+MRSA strains, including the major CA-MRSA clones (USA300, including the LAC strain; USA400; and USA1000), and 11 PVL+methicillin-susceptibleS. aureus(MSSA) strains were tested in microplate culture. Time-kill analyses with ceftobiprole at its MIC were also run with LAC. Efficacies of ceftobiprole (40 mg/kg of body weight subcutaneously [s.c.] four times a day [q.i.d.]) or vancomycin (60 mg/kg intramuscularly [i.m.] twice a day [b.i.d.]) alone or combined with rifampin (10 mg/kg b.i.d.) against rabbit CA-MRSA osteomyelitis, induced by tibial injection of 3.4 × 107CFU of LAC, were compared. Treatment, started 14 days postinoculation, lasted 14 days.In vitro, 6/11 strains cultured with sub-MICs of ceftobiprole produced 1.6- to 4.8-fold more PVL than did the controls, with no link to specific clones. Rifampin decreased PVL production by all tested strains. In time-kill analyses at the LAC MIC (0.75 mg/liter), PVL production rose transiently at 6 and 8 h and then declined 2-fold at 16 h, concomitant with a 2-log10-CFU-count decrease.In vivo, the mean log10CFU/g of bone for ceftobiprole (1.44 ± 0.40) was significantly lower than that for vancomycin (2.37 ± 1.22) (P= 0.034), with 7/10 versus 5/11 bones sterilized, respectively. Combination with rifampin enhanced ceftobiprole (1.16 ± 0.04 CFU/g of bone [P= 0.056], 11/11 sterile bones) and vancomycin (1.23 ± 0.06 CFU/g [P= 0.011], 11/11 sterile bones) efficacies. Ceftobiprole bactericidal activity and the rifampin anti-PVL effect could play a role in these findings, which should be of interest for treating CA-MRSA osteomyelitis.

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