scholarly journals Biological activity of manganese(i) tricarbonyl complexes on multidrug-resistant Gram-negative bacteria: From functional studies to in vivo activity in Galleria mellonella

Metallomics ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 2033-2042 ◽  
Author(s):  
Paul Güntzel ◽  
Christoph Nagel ◽  
Jeanette Weigelt ◽  
Jono W. Betts ◽  
Calum A. Pattrick ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Biological Activity ◽  
Galleria Mellonella ◽  
Atp Release ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Bacterial Clearance ◽  
Gram Negative ◽  
Functional Studies

Antibacterial activity of four Mn(CO)3 complexes on multidrug-resistant clinical isolates of A. baumannii and P. aeruginosa correlated with lipophilicity and increase in ATP release. Absence of host toxicity in G. mellonella was combined with effective bacterial clearance.

scholarly journals Efficacy of Humanized Exposures of Cefiderocol (S-649266) against a Diverse Population of Gram-Negative Bacteria in a Murine Thigh Infection Model

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Marguerite L. Monogue ◽  
Masakatsu Tsuji ◽  
Yoshinori Yamano ◽  
Roger Echols ◽  
David P. Nicolau
Keyword(s):  
Antibacterial Activity ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Gram Negative Bacteria ◽  
Diverse Population ◽  
Gram Negative ◽  
Content Type ◽  
Log Reduction

ABSTRACT Cefiderocol (S-649266) is a novel siderophore cephalosporin with potent in vitro activity against clinically encountered multidrug-resistant (MDR) Gram-negative isolates; however, its spectrum of antibacterial activity against these difficult-to-treat isolates remains to be fully explored in vivo. Here, we evaluated the efficacy of cefiderocol humanized exposures in a neutropenic murine thigh model to support a suitable MIC breakpoint. Furthermore, we compared cefiderocol's efficacy with humanized exposures of meropenem and cefepime against a subset of these phenotypically diverse isolates. Ninety-five Gram-negative isolates were studied. Efficacy was determined as the change in log10 CFU at 24 h compared with 0-h controls. Bacterial stasis or ≥1 log reduction in 67 isolates with MICs of ≤4 μg/ml was noted in 77, 88, and 85% of Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa, respectively. For isolates with MICs of ≥8 μg/ml, bacterial stasis or ≥1 log10 reduction was observed in only 2 of 28 (8 Enterobacteriaceae, 19 A. baumannii, and 1 P. aeruginosa) strains. Against highly resistant meropenem and cefepime organisms, cefiderocol maintained its in vivo efficacy. Overall, humanized exposures of cefiderocol produced similar reductions in bacterial density for organisms with MICs of ≤4 μg/ml, whereas isolates with MICs of ≥8 μg/ml generally displayed bacterial growth in the presence of the compound. Data derived in the current study will assist with the delineation of MIC susceptibility breakpoints for cefiderocol against these important nosocomial Gram-negative pathogens; however, additional clinical data are required to substantiate these observations.

scholarly journals Reversion of antibiotic resistance in multidrug-resistant pathogens using non-antibiotic pharmaceutical benzydamine

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Yuan Liu ◽  
Ziwen Tong ◽  
Jingru Shi ◽  
Yuqian Jia ◽  
Tian Deng ◽  
...  
Keyword(s):  
Cost Effective ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Treatment Regimens ◽  
Development Of Resistance ◽  
Metabolic States ◽  
Animal Infection ◽  
Life Threatening

AbstractAntimicrobial resistance has been a growing concern that gradually undermines our tradition treatment regimens. The fact that few antibacterial drugs with new scaffolds or targets have been approved in the past two decades aggravates this crisis. Repurposing drugs as potent antibiotic adjuvants offers a cost-effective strategy to mitigate the development of resistance and tackle the increasing infections by multidrug-resistant (MDR) bacteria. Herein, we found that benzydamine, a widely used non‐steroidal anti‐inflammatory drug in clinic, remarkably potentiated broad-spectrum antibiotic-tetracyclines activity against a panel of clinically important pathogens, including MRSA, VRE, MCRPEC and tet(X)-positive Gram-negative bacteria. Mechanistic studies showed that benzydamine dissipated membrane potential (▵Ψ) in both Gram-positive and Gram-negative bacteria, which in turn upregulated the transmembrane proton gradient (▵pH) and promoted the uptake of tetracyclines. Additionally, benzydamine exacerbated the oxidative stress by triggering the production of ROS and suppressing GAD system-mediated oxidative defensive. This mode of action explains the great bactericidal activity of the doxycycline-benzydamine combination against different metabolic states of bacteria involve persister cells. As a proof-of-concept, the in vivo efficacy of this drug combination was evidenced in multiple animal infection models. These findings indicate that benzydamine is a potential tetracyclines adjuvant to address life-threatening infections by MDR bacteria.

scholarly journals Mechanistic Understanding Enables the Rational Design of Salicylanilide Combination Therapies for Gram-Negative Infections

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Janine N. Copp ◽  
Daniel Pletzer ◽  
Alistair S. Brown ◽  
Joris Van der Heijden ◽  
Charlotte M. Miton ◽  
...  
Keyword(s):  
Rational Design ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Gram Negative Bacteria ◽  
Combination Therapies ◽  
Diverse Range ◽  
Gram Negative ◽  
Mechanistic Understanding ◽  
Multiple Drugs

ABSTRACT One avenue to combat multidrug-resistant Gram-negative bacteria is the coadministration of multiple drugs (combination therapy), which can be particularly promising if drugs synergize. The identification of synergistic drug combinations, however, is challenging. Detailed understanding of antibiotic mechanisms can address this issue by facilitating the rational design of improved combination therapies. Here, using diverse biochemical and genetic assays, we examine the molecular mechanisms of niclosamide, a clinically approved salicylanilide compound, and demonstrate its potential for Gram-negative combination therapies. We discovered that Gram-negative bacteria possess two innate resistance mechanisms that reduce their niclosamide susceptibility: a primary mechanism mediated by multidrug efflux pumps and a secondary mechanism of nitroreduction. When efflux was compromised, niclosamide became a potent antibiotic, dissipating the proton motive force (PMF), increasing oxidative stress, and reducing ATP production to cause cell death. These insights guided the identification of diverse compounds that synergized with salicylanilides when coadministered (efflux inhibitors, membrane permeabilizers, and antibiotics that are expelled by PMF-dependent efflux), thus suggesting that salicylanilide compounds may have broad utility in combination therapies. We validate these findings in vivo using a murine abscess model, where we show that niclosamide synergizes with the membrane permeabilizing antibiotic colistin against high-density infections of multidrug-resistant Gram-negative clinical isolates. We further demonstrate that enhanced nitroreductase activity is a potential route to adaptive niclosamide resistance but show that this causes collateral susceptibility to clinical nitro-prodrug antibiotics. Thus, we highlight how mechanistic understanding of mode of action, innate/adaptive resistance, and synergy can rationally guide the discovery, development, and stewardship of novel combination therapies. IMPORTANCE There is a critical need for more-effective treatments to combat multidrug-resistant Gram-negative infections. Combination therapies are a promising strategy, especially when these enable existing clinical drugs to be repurposed as antibiotics. We examined the mechanisms of action and basis of innate Gram-negative resistance for the anthelmintic drug niclosamide and subsequently exploited this information to demonstrate that niclosamide and analogs kill Gram-negative bacteria when combined with antibiotics that inhibit drug efflux or permeabilize membranes. We confirm the synergistic potential of niclosamide in vitro against a diverse range of recalcitrant Gram-negative clinical isolates and in vivo in a mouse abscess model. We also demonstrate that nitroreductases can confer resistance to niclosamide but show that evolution of these enzymes for enhanced niclosamide resistance confers a collateral sensitivity to other clinical antibiotics. Our results highlight how detailed mechanistic understanding can accelerate the evaluation and implementation of new combination therapies.

scholarly journals Combining Colistin with Furanone C-30 Rescues Colistin Resistance of Gram-Negative Bacteria in Vitro and in Vivo

2021 ◽  
Author(s):  
Ying Zhang ◽  
Yishuai Lin ◽  
Xiaodong Zhang ◽  
Liqiong Chen ◽  
Chunyan Xu ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Gram Negative Bacteria ◽  
Colistin Resistance ◽  
Gram Negative ◽  
C 30

Colistin is among the few antibiotics effective against multidrug-resistant Gram-negative bacteria (GNB) clinical isolates. However, colistin-resistant GNB strains have emerged in recent years.

scholarly journals A multifunctional platform with single-NIR-laser-triggered photothermal and NO release for synergistic therapy against multidrug-resistant Gram-negative bacteria and their biofilms

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Baohua Zhao ◽  
He Wang ◽  
Wenjing Dong ◽  
Shaowen Cheng ◽  
Haisheng Li ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Bacterial Cell ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
No Release ◽  
Bacterial Cell Membrane ◽  
Multifunctional Platform ◽  
Nir Laser

Abstract Background Infectious diseases caused by multidrug-resistant (MDR) bacteria, especially MDR Gram-negative strains, have become a global public health challenge. Multifunctional nanomaterials for controlling MDR bacterial infections via eradication of planktonic bacteria and their biofilms are of great interest. Results In this study, we developed a multifunctional platform (TG-NO-B) with single NIR laser-triggered PTT and NO release for synergistic therapy against MDR Gram-negative bacteria and their biofilms. When located at the infected sites, TG-NO-B was able to selectively bind to the surfaces of Gram-negative bacterial cells and their biofilm matrix through covalent coupling between the BA groups of TG-NO-B and the bacterial LPS units, which could greatly improve the antibacterial efficiency, and reduce side damages to ambient normal tissues. Upon single NIR laser irradiation, TG-NO-B could generate hyperthermia and simultaneously release NO, which would synergistically disrupt bacterial cell membrane, further cause leakage and damage of intracellular components, and finally induce bacteria death. On one hand, the combination of NO and PTT could largely improve the antibacterial efficiency. On the other hand, the bacterial cell membrane damage could improve the permeability and sensitivity to heat, decrease the photothermal temperature and avoid damages caused by high temperature. Moreover, TG-NO-B could be effectively utilized for synergistic therapy against the in vivo infections of MDR Gram-negative bacteria and their biofilms and accelerate wound healing as well as exhibit excellent biocompatibility both in vitro and in vivo. Conclusions Our study demonstrates that TG-NO-B can be considered as a promising alternative for treating infections caused by MDR Gram-negative bacteria and their biofilms.

scholarly journals In vitro Antibacterial Effect of Medicinal Plants Against Multidrug Resistant Gram Negative Bacteria

2018 ◽  
Vol 5 ◽  
pp. 25-31
Author(s):  
Bishnu Thapa ◽  
Anjana Singh ◽  
Reshma Tuladhar
Keyword(s):  
Antibacterial Activity ◽  
Medicinal Plants ◽  
Multidrug Resistant ◽  
Diffusion Method ◽  
Ocimum Sanctum ◽  
Clinical Samples ◽  
Acorus Calamus ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Herbal Plants

Objectives: The aim of this work was to determine the antibacterial activity of methanol extract of herbal plants against the Multidrug resistant (MDR) Gram negative bacteria isolated from clinical samples. Methods: Gram negative bacteria isolated from various clinical samples were processed for antibiotic susceptibility test by modified Kirby-Bauer disc diffusion method and MDR bacteria were selected. Methanol extracts of six different medicinal plants Acorus calamus (bojho), Ocimum sanctum (tulsi), Azadirachta indica (neem), Cinnamomum tamala (tejpatta), Aloe vera and Zanthoxylum alatum (timur), were tested for antibacterial activity against the selected MDR bacteria by agar well diffusion method. Results: From clinical samples, 8 different MDR Gram negative bacteria isolated were Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Citrobacter spp., Proteus mirabilis, Proteus vulgaris, Acinetobacter spp. and Pseudomonas spp. with E. coli dominated the number. Out of six medicinal plants extracts, Z. alatum, C. tamala and Ocimum sanctum were found to be effective with zones of inhibition ranging from 9-13 mm. The medicinal plants with antibacterial activity can be an alternative source of medicine against MDR Gram negative bacteria. Conclusion: Several herbal plants extracts exhibit antibacterial activity against MDR Gram negative bacteria. Antibacterial activity of plant extracts can vary with type of plant and extraction methods. Thus, for optimal benefit of plant extract, an appropriate extraction method and use of purified product is essential.

scholarly journals Potential Antimicrobial and Chemical Composition of Essential Oils from Piper caldense Tissues

2017 ◽  
Vol 60 (3) ◽  
Author(s):  
Dayane Silva Rocha ◽  
Janete Magali Da Silva ◽  
Daniela Maria Do Amaral Ferraz Navarro ◽  
Claúdio Augusto Gomes Camara ◽  
Camila Soledade De Lira ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Biological Activity ◽  
Chemical Composition ◽  
Essential Oils ◽  
Chemical Constituents ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Gram Positive Bacteria ◽  
Major Chemical ◽  
Antibacterial Potential

The essential oils from leaves, stems and roots of Piper caldense were analyzed by GC-MS. The antibacterial potential of the oils was evaluated against gram-negative bacteria and gram-positive bacteria. The major chemical constituents that were identified from various parts of this plant were α-cardinal, α-muurolol, tujopsan-2-β-ol and δ-cadiene in the leaves, valencene, pentadecane, elina-3,7-11-dieno α-terpineol in the roots and terpine-4-ol, α-terpineol, α-cadinol 2-β-ol in the stems. Tissue oils showed antibacterial activity against the bacteria tested except for Enterococcus faecalis. This is the first report of the biological activity and chemical composition essential oil of P. caldense.

scholarly journals Quinine Enhances Photo-Inactivation of Gram-Negative Bacteria

2019 ◽  
Vol 221 (4) ◽  
pp. 618-626 ◽  
Author(s):  
Leon G Leanse ◽  
Pu-Ting Dong ◽  
Xueping S Goh ◽  
Min Lu ◽  
Ji-Xin Cheng ◽  
...  
Keyword(s):  
Mouse Skin ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Antimicrobial Effects ◽  
Therapeutic Modalities ◽  
Novel Approach

Abstract Background Antimicrobial resistance is a significant concern to public health, and there is a pressing need to develop novel antimicrobial therapeutic modalities. Methods In this study, we investigated the capacity for quinine hydrochloride (Q-HCL) to enhance the antimicrobial effects of antimicrobial blue light ([aBL] 405 nm wavelength) against multidrug-resistant (MDR) Gram-negative bacteria in vitro and in vivo. Results Our findings demonstrated the significant improvement in the inactivation of MDR Pseudomonas aeruginosa and Acinetobacter baumannii (planktonic cells and biofilms) when aBL was illuminated during Q-HCL exposure. Furthermore, the addition of Q-HCL significantly potentiated the antimicrobial effects of aBL in a mouse skin abrasion infection model. In addition, combined exposure of aBL and Q-HCL did not result in any significant apoptosis when exposed to uninfected mouse skin. Conclusions In conclusion, aBL in combination with Q-HCL may offer a novel approach for the treatment of infections caused by MDR bacteria.

scholarly journals Using Nanoscopy To Probe the Biological Activity of Antimicrobial Leads That Display Potent Activity against Pathogenic, Multidrug Resistant, Gram-Negative Bacteria

ACS Nano ◽  
2019 ◽  
Vol 13 (5) ◽  
pp. 5133-5146 ◽  
Author(s):  
Kirsty L. Smitten ◽  
Hannah M. Southam ◽  
Jorge Bernardino de la Serna ◽  
Martin R. Gill ◽  
Paul J. Jarman ◽  
...  
Keyword(s):  
Biological Activity ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Gram Negative
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