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 Reversion of antibiotic resistance in drug-resistant bacteria using non-steroidal anti-inflammatory drug benzydamine

2021 ◽  
Author(s):  
Yuan Liu ◽  
Ziwen Tong ◽  
Jingru Shi ◽  
Tian Deng ◽  
Ruichao Li ◽  
...  
Keyword(s):  
Cost Effective ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Inflammatory Drug ◽  
Development Of Resistance ◽  
Drug Resistant Bacteria ◽  
Metabolic States ◽  
Anti Inflammatory ◽  
Approved Drugs

Antimicrobial resistance has been a growing concern that gradually undermines our tradition treatment regimen. The fact that few antibacterial drugs with new scaffolds or targets have been approved in the past two decades aggravates this crisis. Repurposing previously approved 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 clinical important resistant pathogens, including MRSA, VRE, MCRPEC and tet (X)-positive Gram negative bacteria. Further mechanistically experiments showed that benzydamine dissipated membrane potential (ΔΨ) in both Gram positive and negative bacteria, which in turn upregulated the transmembrane proton gradient (ΔpH) 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 including persister cells. As a proof of concept, the in vivo efficacy of this combination therapy was evidenced in multiple animal infection models. These findings revealed that benzydamine is a promising tetracycline antibiotics adjuvant and has the potential to address life threatening infections by MDR bacteria.

scholarly journals A novel chemical biology and computational approach to expedite the discovery of new-generation polymyxins against life-threatening Acinetobacter baumannii

2021 ◽  
Author(s):  
Xukai Jiang ◽  
Nitin A. Patil ◽  
Mohammad A. K. Azad ◽  
Hasini Wickremasinghe ◽  
Heidi Yu ◽  
...  
Keyword(s):  
Public Health ◽  
Chemical Biology ◽  
Multidrug Resistant ◽  
Computational Approach ◽  
Gram Negative Bacteria ◽  
Global Public Health ◽  
Gram Negative ◽  
Life Threatening ◽  
New Generation ◽  
Novel Antibiotics

Multidrug-resistant Gram-negative bacteria have been an urgent threat to global public health. Novel antibiotics are desperately needed to combat these 'superbugs'.

scholarly journals OMN6 a novel bioengineered peptide for the treatment of multidrug resistant Gram negative bacteria

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shira Mandel ◽  
Janna Michaeli ◽  
Noa Nur ◽  
Isabelle Erbetti ◽  
Jonathan Zazoun ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Antimicrobial Agents ◽  
Cyclic Peptide ◽  
Safety Margin ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Antibiotic Resistant ◽  
Gram Negative ◽  
Development Of Resistance ◽  
Cecropin A

AbstractNew antimicrobial agents are urgently needed, especially to eliminate multidrug resistant Gram-negative bacteria that stand for most antibiotic-resistant threats. In the following study, we present superior properties of an engineered antimicrobial peptide, OMN6, a 40-amino acid cyclic peptide based on Cecropin A, that presents high efficacy against Gram-negative bacteria with a bactericidal mechanism of action. The target of OMN6 is assumed to be the bacterial membrane in contrast to small molecule-based agents which bind to a specific enzyme or bacterial site. Moreover, OMN6 mechanism of action is effective on Acinetobacter baumannii laboratory strains and clinical isolates, regardless of the bacteria genotype or resistance-phenotype, thus, is by orders-of-magnitude, less likely for mutation-driven development of resistance, recrudescence, or tolerance. OMN6 displays an increase in stability and a significant decrease in proteolytic degradation with full safety margin on erythrocytes and HEK293T cells. Taken together, these results strongly suggest that OMN6 is an efficient, stable, and non-toxic novel antimicrobial agent with the potential to become a therapy for humans.

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 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 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 Detection of carbapenemase production in Enterobacteriaceae and Pseudomonas species by carbapenemase Nordmann–Poirel test

2019 ◽  
Vol 11 (02) ◽  
pp. 107-110 ◽  
Author(s):  
Morubagal R. Rao ◽  
Pooja Chandrashaker ◽  
Rashmi P. Mahale ◽  
Sowmya G. Shivappa ◽  
Ranjitha S. Gowda ◽  
...  
Keyword(s):  
Cost Effective ◽  
Multidrug Resistant ◽  
Cross Resistance ◽  
Gram Negative Bacteria ◽  
Beta Lactam ◽  
Hospital Acquired Infections ◽  
Beta Lactam Antibiotics ◽  
Pseudomonas Species ◽  
Life Threatening ◽  
Hospital Acquired

Abstract PURPOSE: Multidrug-resistant organisms causing community-acquired and hospital-acquired infections are increasing at a dangerous rate. Carbapenemase-producing Enterobacteriaceae and Pseudomonas species are an important source of concern since these organisms are not only resistant to beta-lactam antibiotics but also show cross-resistance to other groups of antibiotics. In the present study, rapid detection of these carbapenemase-producing Enterobacteriaceae and Pseudomonas species by carbapenemase Nordmann–Poirel (Carba NP) test was evaluated by comparing with modified Hodge test (MHT). MATERIALS AND METHODS: Imipenem-resistant Enterobacteriaceae and Pseudomonas species isolated from various samples such as pus, blood, sputum, urine, and endotracheal aspirates were processed for carbapenemase detection by MHT and Carba NP test. Kappa analysis was done to evaluate the percentage agreement between the two tests. RESULTS: Seventy imipenem-resistant Enterobacteriaceae and Pseudomonas isolates were analyzed in the present study for carbapenemase production. 63.41% ofEnterobacteriaceae and 34.48% of Pseudomonas species were carbapenemase producers considering both the methods. By MHT, 36 (51.42%) isolates and, by Carba NP test, 35 (50%) isolates were positive for carbapenemase production out of the 70 isolates. CONCLUSION: Carba NP test when compared to MHT is a simple, rapid, cost-effective biochemical test which can be used in all laboratories in the identification of life-threatening carbapenemase-producing Gram-negative bacteria.

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 Diversity and Proliferation of Metallo-β-Lactamases: a Clarion Call for Clinically Effective Metallo-β-Lactamase Inhibitors

2018 ◽  
Vol 84 (18) ◽  
Author(s):  
Anou M. Somboro ◽  
John Osei Sekyere ◽  
Daniel G. Amoako ◽  
Sabiha Y. Essack ◽  
Linda A. Bester
Keyword(s):  
Bacterial Infections ◽  
Bacterial Resistance ◽  
Multidrug Resistant ◽  
Gram Negative Bacteria ◽  
Structural Variations ◽  
Gram Negative ◽  
Clinical Phase ◽  
Class B ◽  
Life Threatening ◽  
Made In

ABSTRACTThe worldwide proliferation of life-threatening metallo-β-lactamase (MBL)-producing Gram-negative bacteria is a serious concern to public health. MBLs are compromising the therapeutic efficacies of β-lactams, particularly carbapenems, which are last-resort antibiotics indicated for various multidrug-resistant bacterial infections. Inhibition of enzymes mediating antibiotic resistance in bacteria is one of the major promising means for overcoming bacterial resistance. Compounds having potential MBL-inhibitory activity have been reported, but none are currently under clinical trials. The need for developing safe and efficient MBL inhibitors (MBLIs) is obvious, particularly with the continuous spread of MBLs worldwide. In this review, the emergence and escalation of MBLs in Gram-negative bacteria are discussed. The relationships between different class B β-lactamases identified up to 2017 are represented by a phylogenetic tree and summarized. In addition, approved and/or clinical-phase serine β-lactamase inhibitors are recapitulated to reflect the successful advances made in developing class A β-lactamase inhibitors. Reported MBLIs, their inhibitory properties, and their purported modes of inhibition are delineated. Insights into structural variations of MBLs and the challenges involved in developing potent MBLIs are also elucidated and discussed. Currently, natural products and MBL-resistant β-lactam analogues are the most promising agents that can become clinically efficient MBLIs. A deeper comprehension of the mechanisms of action and activity spectra of the various MBLs and their inhibitors will serve as a bedrock for further investigations that can result in clinically useful MBLIs to curb this global menace.

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