scholarly journals Azidothymidine Produces Synergistic Activity in Combination with Colistin against Antibiotic-Resistant Enterobacteriaceae

2018 ◽  
Vol 63 (1) ◽  
Author(s):  
Yanmin Hu ◽  
Yingjun Liu ◽  
Anthony Coates
Keyword(s):  
Bacterial Infections ◽  
Therapeutic Potential ◽  
Infection Model ◽  
Synergistic Activity ◽  
Antibiotic Resistant ◽  
Content Type ◽  
E Coli ◽  
Broth Microdilution Method ◽  
Peritoneal Infection ◽  
Time Kill

ABSTRACT Bacterial infections remain a leading killer worldwide, which is worsened by the continuous emergence of antibiotic resistance. In particular, antibiotic-resistant Enterobacteriaceae are prevalent and extremely difficult to treat. Repurposing existing drugs and improving the therapeutic potential of existing antibiotics represent an attractive novel strategy. Azidothymidine (AZT) is an antiretroviral drug which is used in combination with other antivirals to prevent and to treat HIV/AIDS. AZT is also active against Gram-negative bacteria but has not been developed for that purpose. Here, we investigated the in vitro and in vivo efficacy of AZT in combination with colistin against antibiotic-resistant Enterobacteriaceae, including strains producing extended-spectrum beta-lactamases (ESBLs) or New Delhi metallo-beta-lactamase 1 (NDM) or carrying mobilized colistin resistance (mcr-1). The MIC was determined using the broth microdilution method. The combined effect of AZT and colistin was examined using the checkerboard method and time-kill analysis. A murine peritoneal infection model was used to test the therapeutic effect of the combination of AZT and colistin. The fractional inhibitory concentration index from the checkerboard assay demonstrated that AZT synergized with colistin against 61% and 87% of ESBL-producing Escherichia coli and Klebsiella pneumoniae strains, respectively, 100% of NDM-1-producing strains, and 92% of mcr-1-producing E. coli strains. Time-kill analysis demonstrated significant synergistic activities when AZT was combined with colistin. In a murine peritoneal infection model, AZT in combination with colistin showed augmented activities of both drugs in the treatment of NDM-1 K. pneumoniae and mcr-1 E. coli infections. The AZT and colistin combination possesses a potential to be used coherently to treat antibiotic-resistant Enterobacteriaceae infections.

scholarly journals Therapeutic Potential of the Antimicrobial Peptide OH-CATH30 for Antibiotic-Resistant Pseudomonas aeruginosa Keratitis

2014 ◽  
Vol 58 (6) ◽  
pp. 3144-3150 ◽  
Author(s):  
Sheng-An Li ◽  
Jie Liu ◽  
Yang Xiang ◽  
Yan-Jie Wang ◽  
Wen-Hui Lee ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Topical Application ◽  
Bacterial Infections ◽  
Therapeutic Potential ◽  
Synergistic Activity ◽  
Drug Resistant ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Checkerboard Assay ◽  
King Cobra

ABSTRACTThe therapeutic potential of antimicrobial peptides (AMPs) has been evaluated in many infectious diseases. However, the topical application of AMPs for ocular bacterial infection has not been well investigated. The AMP OH-CATH30, which was identified in the king cobra, exhibits potent antimicrobial activity. In this study, we investigated the therapeutic potential of OH-CATH30 forPseudomonas aeruginosakeratitis. Ten isolates ofP. aeruginosafrom individuals with keratitis were susceptible to OH-CATH30 but not to cefoperazone, ciprofloxacin, gentamicin, and levofloxacin. The microdilution checkerboard assay showed that OH-CATH30 exhibited synergistic activity with ciprofloxacin and levofloxacin against antibiotic-resistantP. aeruginosa. Meanwhile,P. aeruginosadid not develop resistance to OH-CATH30, even after exposure at 0.5× the MIC for up to 25 subcultures. Furthermore, treatment with OH-CATH30, alone or in combination with levofloxacin, significantly improved the clinical outcomes of rabbit keratitis induced by antibiotic-resistantP. aeruginosa. Taken together, our data indicate that the topical application of OH-CATH30 is efficacious against drug-resistantP. aeruginosakeratitis. In addition, our study highlights the potential application of AMPs in treating ocular bacterial infections.

scholarly journals Activity of Fosfomycin and Amikacin against Fosfomycin-Heteroresistant Escherichia coli Strains in a Hollow-Fiber Infection Model

2021 ◽  
Vol 65 (5) ◽  
Author(s):  
I. Portillo-Calderón ◽  
M. Ortiz-Padilla ◽  
B. de Gregorio-Iaria ◽  
V. Merino-Bohorquez ◽  
J. Blázquez ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Hollow Fiber ◽  
Infection Model ◽  
Bacterial Burden ◽  
Content Type ◽  
E Coli ◽  
Bacterial Cultures ◽  
Agar Dilution ◽  
Time Kill ◽  
Risk Of Treatment

ABSTRACT We evaluated human-like the efficacy of intravenous doses of fosfomycin of 8 g every 8 h (8 g/Q8h) and of amikacin (15 mg/kg/Q24h) in monotherapy and in combination against six fosfomycin-heteroresistant Escherichia coli isolates using a hollow-fiber infection model (HFIM). Six fosfomycin-heteroresistant E. coli isolates (four with strong mutator phenotype) and the control strain E. coli ATCC 25922 were used. Mutant frequencies for rifampin (100 mg/liter), fosfomycin (50 and 200 mg/liter), and amikacin (32 mg/liter) were determined. Fosfomycin and amikacin MICs were assessed by agar dilution (AD), gradient strip assay (GSA), and broth microdilution (BMD). Fosfomycin and amikacin synergies were studied by checkerboard and time-kill assays at different concentrations. The efficacies of fosfomycin (8 g/Q8h) and amikacin (15 mg/kg/Q24h) alone and in combination were assessed using an HFIM. Five isolates were determined to be resistant to fosfomycin by AD and BMD, but all were determined to be susceptible by GSA. All isolates were determined to be susceptible to amikacin. Antibiotic combinations were synergistic in two isolates, and no antagonism was detected. In time-kill assays, all isolates survived under fosfomycin at 64 mg/liter, although at 307 mg/liter only the normomutators and two hypermutators survived. Four isolates survived under 16 mg/liter amikacin, and none survived at 45 mg/liter. No growth was detected under combination conditions. In HFIM, fosfomycin and amikacin monotherapies failed to sterilize bacterial cultures; however, the combination of fosfomycin and amikacin yielded a rapid eradication. There may be a risk of treatment failure of fosfomycin-heteroresistant E. coli isolates using either amikacin or fosfomycin in monotherapy. These results support that the amikacin-fosfomycin combination can rapidly decrease bacterial burden and prevent the emergence of resistant subpopulations against fosfomycin-heteroresistant strains.

scholarly journals Activity of Tigecycline or Colistin in Combination with Zidovudine against Escherichia coli Harboring tet(X) and mcr-1

2020 ◽  
Vol 65 (1) ◽  
pp. e01172-20 ◽  
Author(s):  
Yu-Feng Zhou ◽  
Ping Liu ◽  
Shu-He Dai ◽  
Jian Sun ◽  
Ya-Hong Liu ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Multidrug Resistant ◽  
Therapeutic Options ◽  
Infection Model ◽  
Synergistic Activity ◽  
Colistin Resistance ◽  
Content Type ◽  
E Coli ◽  
Antiretroviral Drug

ABSTRACTAlternative therapeutic options are urgently needed against multidrug-resistant Escherichia coli infections, especially in situations of preexisting tigecycline and colistin resistance. Here, we investigated synergistic activity of the antiretroviral drug zidovudine in combination with tigecycline or colistin against E. coli harboring tet(X) and mcr-1 in vitro and in a murine thigh infection model. Zidovudine and tigecycline/colistin combinations achieved synergistic killing and significantly decreased bacterial burdens by >2.5-log10 CFU/g in thigh tissues compared to each monotherapy.

scholarly journals Synergistic Activity of Colistin Combined With Auranofin Against Colistin-Resistant Gram-Negative Bacteria

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaoxuan Feng ◽  
Shuai Liu ◽  
Yang Wang ◽  
Yulin Zhang ◽  
Lingxiao Sun ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
New Drugs ◽  
Gram Negative Bacteria ◽  
Synergistic Activity ◽  
Gram Negative ◽  
Infection Models ◽  
Potential Alternative ◽  
Peritoneal Infection ◽  
Time Kill ◽  
Rheumatic Drug

Colistin-resistant (Col-R) bacteria are steadily increasing, and are extremely difficult to treat. New drugs or therapies are urgently needed to treat infections caused by these pathogens. Combination therapy with colistin and other old drugs, is an important way to restore the activity of colistin. This study aimed to investigate the activity of colistin in combination with the anti-rheumatic drug auranofin against Col-R Gram-negative bacteria. The results of checkerboard analysis demonstrated that auranofin synergized with colistin against Col-R Gram-negative bacteria. Time-kill assays showed significant synergistic antimicrobial activity of colistin combined with auranofin. Electron microscopy revealed that the combination resulted in more cellular structural alterations compared to each drug alone. Auranofin enhanced the therapeutic effectiveness of colistin in mouse peritoneal infection models. These results suggested that the combination of colistin and auranofin might be a potential alternative for the treatment of Col-R Gram-negative bacterial infections.

scholarly journals Efficacy of OH-CATH30 and Its Analogs against Drug-Resistant BacteriaIn Vitroand in Mouse Models

2012 ◽  
Vol 56 (6) ◽  
pp. 3309-3317 ◽  
Author(s):  
Sheng-An Li ◽  
Wen-Hui Lee ◽  
Yun Zhang
Keyword(s):  
Mouse Models ◽  
Bacterial Infections ◽  
Resistant Bacteria ◽  
Infection Model ◽  
Drug Resistant ◽  
Content Type ◽  
E Coli ◽  
Drug Resistant Bacteria

ABSTRACTAntimicrobial peptides (AMPs) have been considered alternatives to conventional antibiotics for drug-resistant bacterial infections. However, their comparatively high toxicity toward eukaryotic cells and poor efficacyin vivohamper their clinical application. OH-CATH30, a novel cathelicidin peptide deduced from the king cobra, possesses potent antibacterial activityin vitro. The objective of this study is to evaluate the efficacy of OH-CATH30 and its analog OH-CM6 against drug-resistant bacteriain vitroandin vivo. The MICs of OH-CATH30 and OH-CM6 ranged from 1.56 to 12.5 μg/ml against drug-resistant clinical isolates of several pathogenic species, includingEscherichia coli,Pseudomonas aeruginosa, and methicillin-resistantStaphylococcus aureus. The MICs of OH-CATH30 and OH-CM6 were slightly altered in the presence of 25% human serum. OH-CATH30 and OH-CM6 killedE. coliquickly (within 60 min) by disrupting the bacterial cytoplasmic membrane. Importantly, the 50% lethal doses (LD50) of OH-CATH30 and OH-CM6 in mice following intraperitoneal (i.p.) injection were 120 mg/kg of body weight and 100 mg/kg, respectively, and no death was observed at any dose up to 160 mg/kg following subcutaneous (s.c.) injection. Moreover, 10 mg/kg OH-CATH30 or OH-CM6 significantly decreased the bacterial counts as well as the inflammatory response in a mouse thigh infection model and rescued infected mice in a bacteremia model induced by drug-resistantE. coli. Taken together, our findings demonstrate that the natural cathelicidin peptide OH-CATH30 and its analogs exhibit relatively low toxicity and potent efficacy in mouse models, indicating that they may have therapeutic potential against the systemic infections caused by drug-resistant bacteria.

scholarly journals Successful Development of Bacteriocins into Therapeutic Formulation for Treatment of MRSA Skin Infection in a Murine Model

2020 ◽  
Vol 64 (12) ◽  
Author(s):  
Kirill V. Ovchinnikov ◽  
Christian Kranjec ◽  
Tage Thorstensen ◽  
Harald Carlsen ◽  
Dzung B. Diep
Keyword(s):  
Skin Infection ◽  
Therapeutic Potential ◽  
Multidrug Resistant ◽  
Penicillin G ◽  
Infection Model ◽  
Component Mixture ◽  
Antibiotic Resistant ◽  
Content Type ◽  
Infection Treatment

ABSTRACT The emergence of antibiotic-resistant pathogens has caused a serious worldwide problem in infection treatment in recent years. One of the pathogens is methicillin-resistant Staphylococcus aureus (MRSA), which is a major cause of skin and soft tissue infections. Alternative strategies and novel sources of antimicrobials to solve antibiotic resistance problems are urgently needed. In this study, we explored the potential of two broad-spectrum bacteriocins, garvicin KS and micrococcin P1, in skin infection treatments. The two bacteriocins acted synergistically with each other and with penicillin G in killing MRSA in vitro. The MICs of the antimicrobials in the three-component mixture were 40 ng/ml for micrococcin P1 and 2 μg/ml for garvicin KS and penicillin G, which were 62, 16, and at least 1,250 times lower than their MICs when assessed individually. To assess its therapeutic potential further, we challenged the three-component formulation in a murine skin infection model with the multidrug-resistant luciferase-tagged MRSA Xen31, a strain derived from the clinical isolate S. aureus ATCC 33591. Using the tagged-luciferase activity as a reporter for the presence of Xen31 in wounds, we demonstrated that the three-component formulation was efficient in eradicating the pathogen from treated wounds. Furthermore, compared to Fucidin cream, which is an antibiotic commonly used in skin infection treatments, our formulation was also superior in terms of preventing resistance development.

scholarly journals Isolation of Phage Lysins That Effectively KillPseudomonas aeruginosain Mouse Models of Lung and Skin Infection

2019 ◽  
Vol 63 (7) ◽  
Author(s):  
Assaf Raz ◽  
Anna Serrano ◽  
Anaise Hernandez ◽  
Chad W. Euler ◽  
Vincent A. Fischetti
Keyword(s):  
Outer Membrane ◽  
Bacterial Infections ◽  
Skin Infection ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Opportunistic Pathogen ◽  
Infection Model ◽  
Gram Negative ◽  
Content Type ◽  
Phage Lysins

ABSTRACTMultidrug resistance (MDR) is rapidly increasing in prevalence among isolates of the opportunistic pathogenPseudomonas aeruginosa, leaving few treatment options. Phage lysins are cell wall hydrolases that have a demonstrated therapeutic potential against Gram-positive pathogens; however, the outer membrane of Gram-negative bacteria prevents most lysins from reaching the peptidoglycan, making them less effective as therapeutics. Nevertheless, a few lysins from Gram-negative bacterial phage can penetrate the bacterial outer membrane with the aid of an amphipathic tail found in the molecule’s termini. In this work, we took a phylogenetic approach to systematically identify those lysins fromP. aeruginosaphage that would be most effective therapeutically. We isolated and performed preliminary characterization of 16 lysins and chose 2 lysins, PlyPa03 and PlyPa91, which exhibited >5-log killing activity againstP. aeruginosaand other Gram-negative pathogens (particularlyKlebsiellaandEnterobacter). These lysins showed rapid killing kinetics and were active in the presence of high concentrations of salt and urea and under pH conditions ranging from 5.0 to 10.0. Activity was not inhibited in the presence of the pulmonary surfactant beractant (Survanta). While neither enzyme was active in 100% human serum, PlyPa91 retained activity in low serum concentrations. The lysins were effective in the treatment of aP. aeruginosaskin infection in a mouse model, and PlyPa91 protected mice in a lung infection model, making these lysins potential drug candidates for Gram-negative bacterial infections of the skin or respiratory mucosa.

scholarly journals Equisetin Restores Colistin Sensitivity against Multi-Drug Resistant Gram-Negative Bacteria

Antibiotics ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1263
Author(s):  
Qi Zhang ◽  
Shang Chen ◽  
Xiaojia Liu ◽  
Wenhan Lin ◽  
Kui Zhu
Keyword(s):  
Synergistic Effect ◽  
New Drugs ◽  
Infection Model ◽  
Gram Negative Bacteria ◽  
Synergistic Activity ◽  
Drug Resistant ◽  
Gram Negative ◽  
E Coli ◽  
Hydrophobic Barrier ◽  
Time Kill

The overuse of antibiotics and the scarcity of new drugs have led to a serious antimicrobial resistance crisis, especially for multi-drug resistant (MDR) Gram-negative bacteria. In the present study, we investigated the antimicrobial activity of a marine antibiotic equisetin in combination with colistin against Gram-negative bacteria and explored the mechanisms of synergistic activity. We tested the synergistic effect of equisetin in combination with colistin on 23 clinical mcr-1 positive isolates and found that 4 µg/mL equisetin combined with 1 µg/mL colistin showed 100% inhibition. Consistently, equisetin restored the sensitivity of 10 species of mcr-1 positive Gram-negative bacteria to colistin. The combination of equisetin and colistin quickly killed 99.9% bacteria in one hour in time-kill assays. We found that colistin promoted intracellular accumulation of equisetin in colistin-resistant E. coli based on LC-MS/MS analysis. Interestingly, equisetin boosted ROS accumulation in E. coli in the presence of colistin. Moreover, we found that equisetin and colistin lost the synergistic effect in two LPS-deficient A. baumannii strains. These findings suggest that colistin destroys the hydrophobic barrier of Gram-negative bacteria, facilitating equisetin to enter the cell and exert its antibacterial effect. Lastly, equisetin restored the activity of colistin in a G. mellonella larvae infection model. Collectively, these results reveal that equisetin can potentiate colistin activity against MDR Gram-negative bacteria including colistin-resistant strains, providing an alternative approach to address Gram-negative pathogens associated with infections in clinics.

Repurposing of auranofin against bacterial infections: An In silico and In vitro study

2020 ◽  
Vol 16 ◽  
Author(s):  
Nidhi Sharma ◽  
Arti Singh ◽  
Ruchika Sharma ◽  
Anoop Kumar
Keyword(s):  
Broad Spectrum ◽  
In Silico ◽  
Antibacterial Agent ◽  
Bacterial Infections ◽  
In Vitro Assays ◽  
Infection Model ◽  
Synergistic Activity ◽  
Bacterial Strains ◽  
Molecular Docking Study

Aim: The aim of the study was to find out the role of auranofin as a promising broad spectrum antibacterial agent. Methods: In-vitro assays (Percentage growth retardation, Bacterial growth kinetics, Biofilm formation assay) and In-silico study (Molegro virtual docker (MVD) version 6.0 and Molecular operating environment (MOE) version 2008.10 software). Results: The in vitro assays have shown that auranofin has good antibacterial activity against Gram positive and Gram negative bacterial strains. Further, auranofin has shown synergistic activity in combination with ampicillin against S. aureus and B. subtilis whereas in combination with neomycin has just shown additive effect against E. coli, P. aeruginosa and B. pumilus. In vivo results have revealed that auranofin alone and in combination with standard drugs significantly decreased the bioburden in zebrafish infection model as compared to control. The molecular docking study have shown good interaction of auranofin with penicillin binding protein (2Y2M), topoisomerase (3TTZ), UDP-3-O-[3- hydroxymyristoyl] N-acetylglucosaminedeacetylase (3UHM), cell adhesion protein (4QRK), β-lactamase (5CTN) and arylsulphatase (1HDH) enzyme as that of reference ligand which indicate multimodal mechanism of action of auranofin. Finally, MTT assay has shown non-cytotoxic effect of auranofin. Conclusion: In conclusion, auranofin in combination with existing antibiotics could be developed as a broad spectrum antibacterial agent; however, further studies are required to confirm its safety and efficacy. This study provides possibility of use of auranofin apart from its established therapeutic indication in combination with existing antibiotics to tackle the problem of resistance.

scholarly journals Mechanistic insights into synergy between nalidixic acid and tetracycline against clinical isolates of Acinetobacter baumannii and Escherichia coli

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Amit Gaurav ◽  
Varsha Gupta ◽  
Sandeep K. Shrivastava ◽  
Ranjana Pathania
Keyword(s):  
Escherichia Coli ◽  
Acinetobacter Baumannii ◽  
Nalidixic Acid ◽  
Bacterial Infections ◽  
Clinical Isolates ◽  
Hospital Environment ◽  
Infection Model ◽  
Drug Resistant ◽  
E Coli

AbstractThe increasing prevalence of antimicrobial resistance has become a global health problem. Acinetobacter baumannii is an important nosocomial pathogen due to its capacity to persist in the hospital environment. It has a high mortality rate and few treatment options. Antibiotic combinations can help to fight multi-drug resistant (MDR) bacterial infections, but they are rarely used in the clinics and mostly unexplored. The interaction between bacteriostatic and bactericidal antibiotics are mostly reported as antagonism based on the results obtained in the susceptible model laboratory strain Escherichia coli. However, in the present study, we report a synergistic interaction between nalidixic acid and tetracycline against clinical multi-drug resistant A. baumannii and E. coli. Here we provide mechanistic insight into this dichotomy. The synergistic combination was studied by checkerboard assay and time-kill curve analysis. We also elucidate the mechanism behind this synergy using several techniques such as fluorescence spectroscopy, flow cytometry, fluorescence microscopy, morphometric analysis, and real-time polymerase chain reaction. Nalidixic acid and tetracycline combination displayed synergy against most of the MDR clinical isolates of A. baumannii and E. coli but not against susceptible isolates. Finally, we demonstrate that this combination is also effective in vivo in an A. baumannii/Caenorhabditis elegans infection model (p < 0.001)

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