Complex Effects of Macrolide Venturicidins on Bacterial F-ATPases Likely Contribute to Their Action as Antibiotic Adjuvants

2021 ◽  
Author(s):  
Yakov M. Milgrom ◽  
Thomas M. Duncan
Keyword(s):  
Atpase Activity ◽  
Atp Synthase ◽  
Critical Factor ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Adjuvant Activity ◽  
Bacterial Membranes ◽  
Resistant Tuberculosis ◽  
Key Factor ◽  
New Antibiotics

Abstract Bacterial energy metabolism is now recognized as a critical factor for the efficacy of antibiotics. The F-type ATPase/ATP synthase (FOF1) is a central player in cellular bioenergetics of bacteria and eukaryotes, and its potential as a selective antibiotic target has been confirmed by the success of bedaquiline in combatting multidrug-resistant tuberculosis. Venturicidin macrolides were initially identified for their antifungal properties and were found to specifically inhibit FOF1 of eukaryotes and bacteria. Venturicidins alone are not effective antibacterials but recently were found to have adjuvant activity, potentiating the efficacy of aminoglycoside antibiotics against several species of resistant bacteria. Here we discovered more complex effects of venturicidins on the ATPase activity of FOF1 in bacterial membranes from Escherichia coli and Pseudomonas aeruginosa. Our major finding is that higher concentrations of venturicidin induce time– and ATP–dependent decoupling of F1-ATPase activity from the venturicidin-inhibited, proton-transporting FO complex. This dysregulated ATPase activity is likely to be a key factor in the depletion of cellular ATP induced by venturicidins in prior studies with P. aeruginosa and Staphylococcus aureus. Further studies of how this functional decoupling occurs could guide development of new antibiotics and/or adjuvants that target the F-type ATPase/ATP synthase.

scholarly journals Complex effects of macrolide venturicidins on bacterial F-ATPases likely contribute to their action as antibiotic adjuvants

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yakov M. Milgrom ◽  
Thomas M. Duncan
Keyword(s):  
Atpase Activity ◽  
Atp Synthase ◽  
Critical Factor ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Adjuvant Activity ◽  
Bacterial Membranes ◽  
Resistant Tuberculosis ◽  
Key Factor ◽  
New Antibiotics

AbstractBacterial energy metabolism is now recognized as a critical factor for the efficacy of antibiotics. The F-type ATPase/ATP synthase (FOF1) is a central player in cellular bioenergetics of bacteria and eukaryotes, and its potential as a selective antibiotic target has been confirmed by the success of bedaquiline in combatting multidrug-resistant tuberculosis. Venturicidin macrolides were initially identified for their antifungal properties and were found to specifically inhibit FOF1 of eukaryotes and bacteria. Venturicidins alone are not effective antibacterials but recently were found to have adjuvant activity, potentiating the efficacy of aminoglycoside antibiotics against several species of resistant bacteria. Here we discovered more complex effects of venturicidins on the ATPase activity of FOF1 in bacterial membranes from Escherichia coli and Pseudomonas aeruginosa. Our major finding is that higher concentrations of venturicidin induce time– and ATP–dependent decoupling of F1-ATPase activity from the venturicidin-inhibited, proton-transporting FO complex. This dysregulated ATPase activity is likely to be a key factor in the depletion of cellular ATP induced by venturicidins in prior studies with P. aeruginosa and Staphylococcus aureus. Further studies of how this functional decoupling occurs could guide development of new antibiotics and/or adjuvants that target the F-type ATPase/ATP synthase.

scholarly journals Multidrug and Pan-Antibiotic Resistance—The Role of Antimicrobial and Synergistic Essential Oils: A Review

2020 ◽  
Vol 15 (10) ◽  
pp. 1934578X2096259
Author(s):  
Karen Boren ◽  
AliceAnn Crown ◽  
Richard Carlson
Keyword(s):  
Essential Oils ◽  
Bacterial Resistance ◽  
Fungal Infections ◽  
Multidrug Resistant ◽  
World Health ◽  
Resistant Bacteria ◽  
Bacterial Membranes ◽  
New Antibiotics ◽  
Clinical Benefits

Bacterial resistance to antibiotics continues to be a grave threat to human health. Because antibiotics are no longer a lucrative market for pharmaceutical companies, the development of new antibiotics has slowed to a crawl. The World Health Organization reported that the 8 new bacterial agents approved since July 2017 had limited clinical benefits. While a cohort of biopharmaceutical companies recently announced plans to develop 2-4 new antibiotics by 2030, we needn’t wait a decade to find innovative antibiotic candidates. Essential oils (EOs) have long been known as antibacterial agents with wide-ranging arsenals. Many are able to penetrate the bacterial membrane and may also be effective against bacterial defenses such as biofilms, efflux pumps, and quorum sensing. EOs have been documented to fight drug-resistant bacteria alone and/or combined with antibiotics. This review will summarize research showing the significant role of EOs as nonconventional regimens against the worldwide spread of antibiotic-resistant pathogens. The authors conducted a 4-year search of the US National Library of Medicine (PubMed) for relevant EO studies against methicillin-resistant Staphylococcus aureus, multidrug-resistant (MDR) Escherichia coli, EO combinations/synergy with antibiotics, against MDR fungal infections, showing the ability to permeate bacterial membranes, and against the bacterial defenses listed above. EOs are readily available and are a needed addition to the arsenal against resistant pathogens.

scholarly journals Membrane-Activating Triphenylphosphonium Functionalized Ciprofloxacin for Multidrug Resistant Bacteria

2020 ◽  
Author(s):  
Sangrim Kang ◽  
Kyoung Sunwoo ◽  
Yuna Jung ◽  
Junho Hur ◽  
Ki-Ho Park ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Morphological Changes ◽  
Antibacterial Activities ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Severe Problem ◽  
Bacterial Membranes ◽  
High Antibacterial Activity ◽  
New Antibiotics ◽  
Mrsa Strains

Multidrug resistant (MDR) bacteria have become a severe problem for public health. Developing new antibiotics for MDR bacteria is difficult, from inception to the clinically approved stage. Here, we have used a new approach; we have modified the antibiotic, ciprofloxacin (CFX), with triphenylphosphonium (TPP, PPh3) moiety via ester- (CFX-ester-PPh3) and amide-coupling (CFX-ester-PPh3), to target bacterial membranes. In this study, we have evaluated the antibacterial activities of CFX and its derivatives against 16 species of bacteria, including MDR bacteria, using minimum inhibitory concentration (MIC) assay, morphological monitoring, and expression of resistance-related genes. TPP-conjugated CFX, CFX-ester-PPh3 and CFX-amide-PPh3 showed significantly improved antibacterial activity against Gram-positive bacteria, Staphylococcus aureus, including MDR S. aureus (MRSA) strains. The MRSA ST5 5016 strain showed high antibacterial activity, with an MIC values of 11.12 µg/mL for CFX-ester-PPh3 and 2.78 µg/mL for CFX-amide-PPh3. The CFX derivatives inhibited biofilm formation in MRSA by more than 74.9% of CFX-amide-PPh3. In the sub-MIC, CFX derivates induced significant morphological changes in MRSA, including irregular deformation and membrane disruption, accompanied by a decrease in the level of resistance-related gene expression. With these promising results, this method is very likely to combat MDR bacteria, through a simple TPP moiety modification of known antibiotics, which can be readily prepared at clinical sites.

scholarly journals Protein–protein interactions in bacteria: a promising and challenging avenue towards the discovery of new antibiotics

2018 ◽  
Vol 14 ◽  
pp. 2881-2896 ◽  
Author(s):  
Laura Carro
Keyword(s):  
Protein Interactions ◽  
Bacterial Infections ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Protein Protein Interactions ◽  
Lead Discovery ◽  
Antibiotic Development ◽  
Cellular Processes ◽  
Ppi Networks ◽  
New Antibiotics

Antibiotics are potent pharmacological weapons against bacterial infections; however, the growing antibiotic resistance of microorganisms is compromising the efficacy of the currently available pharmacotherapies. Even though antimicrobial resistance is not a new problem, antibiotic development has failed to match the growth of resistant pathogens and hence, it is highly critical to discover new anti-infective drugs with novel mechanisms of action which will help reducing the burden of multidrug-resistant microorganisms. Protein–protein interactions (PPIs) are involved in a myriad of vital cellular processes and have become an attractive target to treat diseases. Therefore, targeting PPI networks in bacteria may offer a new and unconventional point of intervention to develop novel anti-infective drugs which can combat the ever-increasing rate of multidrug-resistant bacteria. This review describes the progress achieved towards the discovery of molecules that disrupt PPI systems in bacteria for which inhibitors have been identified and whose targets could represent an alternative lead discovery strategy to obtain new anti-infective molecules.

scholarly journals Resistance of Gram-Positive Bacteria to Current Antibacterial Agents and Overcoming Approaches

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2888 ◽  
Author(s):  
Buthaina Jubeh ◽  
Zeinab Breijyeh ◽  
Rafik Karaman
Keyword(s):  
Turning Point ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Gram Positive ◽  
Medical Interventions ◽  
Gram Positive Bacteria ◽  
New Antibiotics ◽  
Vancomycin Resistant ◽  
New Treatments ◽  
Emergence Of Resistance

The discovery of antibiotics has created a turning point in medical interventions to pathogenic infections, but unfortunately, each discovery was consistently followed by the emergence of resistance. The rise of multidrug-resistant bacteria has generated a great challenge to treat infections caused by bacteria with the available antibiotics. Today, research is active in finding new treatments for multidrug-resistant pathogens. In a step to guide the efforts, the WHO has published a list of the most dangerous bacteria that are resistant to current treatments and requires the development of new antibiotics for combating the resistance. Among the list are various Gram-positive bacteria that are responsible for serious healthcare and community-associated infections. Methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus faecium, and drug-resistant Streptococcus pneumoniae are of particular concern. The resistance of bacteria is an evolving phenomenon that arises from genetic mutations and/or acquired genomes. Thus, antimicrobial resistance demands continuous efforts to create strategies to combat this problem and optimize the use of antibiotics. This article aims to provide a review of the most critical resistant Gram-positive bacterial pathogens, their mechanisms of resistance, and the new treatments and approaches reported to circumvent this problem.

scholarly journals Thermo-responsive triple-function nanotransporter for efficient chemo-photothermal therapy of multidrug-resistant bacterial infection

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Guangchao Qing ◽  
Xianxian Zhao ◽  
Ningqiang Gong ◽  
Jing Chen ◽  
Xianlei Li ◽  
...  
Keyword(s):  
Near Infrared ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Limited Effect ◽  
Bacterial Membranes ◽  
Change Mechanism ◽  
Drug Resistant Bacteria ◽  
New Strategies

Abstract New strategies with high antimicrobial efficacy against multidrug-resistant bacteria are urgently desired. Herein, we describe a smart triple-functional nanostructure, namely TRIDENT (Thermo-Responsive-Inspired Drug-Delivery Nano-Transporter), for reliable bacterial eradication. The robust antibacterial effectiveness is attributed to the integrated fluorescence monitoring and synergistic chemo-photothermal killing. We notice that temperature rises generated by near-infrared irradiation did not only melt the nanotransporter via a phase change mechanism, but also irreversibly damaged bacterial membranes to facilitate imipenem permeation, thus interfering with cell wall biosynthesis and eventually leading to rapid bacterial death. Both in vitro and in vivo evidence demonstrate that even low doses of imipenem-encapsulated TRIDENT could eradicate clinical methicillin-resistant Staphylococcus aureus, whereas imipenem alone had limited effect. Due to rapid recovery of infected sites and good biosafety we envision a universal antimicrobial platform to fight against multidrug-resistant or extremely drug-resistant bacteria.

scholarly journals Multidrug-Resistant Bacteria Isolated from Different Aquatic Environments in the North of Spain and South of France

2020 ◽  
Vol 8 (9) ◽  
pp. 1425
Author(s):  
Lara Pérez-Etayo ◽  
David González ◽  
José Leiva ◽  
Ana Isabel Vitas
Keyword(s):  
Wastewater Treatment Plants ◽  
Multidrug Resistant ◽  
World Health ◽  
Resistant Bacteria ◽  
Aquatic Environments ◽  
Multidrug Resistant Bacteria ◽  
Antibiotic Resistant ◽  
The North ◽  
New Antibiotics ◽  
Health Organization

Due to the global progress of antimicrobial resistance, the World Health Organization (WHO) published the list of the antibiotic-resistant “priority pathogens” in order to promote research and development of new antibiotics to the families of bacteria that cause severe and often deadly infections. In the framework of the One Health approach, the surveillance of these pathogens in different environments should be implemented in order to analyze their spread and the potential risk of transmission of antibiotic resistances by food and water. Therefore, the objective of this work was to determine the presence of high and critical priority pathogens included in the aforementioned list in different aquatic environments in the POCTEFA area (North Spain–South France). In addition to these pathogens, detection of colistin-resistant Enterobacteriaceae was included due its relevance as being the antibiotic of choice to treat infections caused by multidrug resistant bacteria (MDR). From the total of 80 analyzed samples, 100% of the wastewater treatment plants (WWTPs) and collectors (from hospitals and slaughterhouses) and 96.4% of the rivers, carried antibiotic resistant bacteria (ARB) against the tested antibiotics. Fifty-five (17.7%) of the isolates were identified as target microorganisms (high and critical priority pathogens of WHO list) and 58.2% (n = 32) of them came from WWTPs and collectors. Phenotypic and genotypic characterization showed that 96.4% were MDR and resistance to penicillins/cephalosporins was the most widespread. The presence of bla genes, KPC-type carbapenemases, mcr-1 and vanB genes has been confirmed. In summary, the presence of clinically relevant MDR bacteria in the studied aquatic environments demonstrates the need to improve surveillance and treatments of wastewaters from slaughterhouses, hospitals and WWTPs, in order to minimize the dispersion of resistance through the effluents of these areas.

scholarly journals Multidrug-Resistant Tuberculosis in Children: A Single-Center Experience

2020 ◽  
Vol 54 (4) ◽  
pp. 208-214
Author(s):  
Deniz Aygün ◽  
Tarık Yıldırım ◽  
Özlem Başoğlu Öner ◽  
Sezer Toprak ◽  
Aylin Babalık ◽  
...  
Keyword(s):  
Family Members ◽  
Treatment Protocol ◽  
Multidrug Resistant ◽  
Nucleic Acid Amplification ◽  
Resistant Bacteria ◽  
Single Center Experience ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Total Treatment ◽  
Mdr Tb

Objective: Resistance to at least isoniazid and rifampicin, which are the most important drugs in TB treatment, is called multidrug-resistant tuberculosis (MDR-TB). MDR-TB is a life-threatening condition that affects children as well as adults. Material and Methods: The medical records of children diagnosed with MDR-TB between June 2015 and October 2018 were analyzed retrospectively. Results: Seven female (77.8%) and two male (22.2%) patients were included into the study. Their mean age was 11.58 ± 4.23 years (3.75-15 years). Five patients (55.5%) had family members with MDR-TB. All of them had pulmonary tuberculosis. Acid-resistant bacteria (ARB) were observed in three (33.3%) patients, nucleic acid amplification tests were positive in four (44.4%) patients, and positive cultures were observed in seven (77.7%) patients. Seven patients had microbiologically and two patients had clinically confirmed MDR-TB. Five patients (55.5%) had isoniazid and rifampicin resistance, two patients (22.2%) had isoniazid, rifampicin and streptomycin resistance. A treatment protocol consisting of pyrazinamide, ethambutol, amikacin, protionamide and moxifloxacin was started after evaluating the culture results of the patients and family members. Cycloserine was added to the treatment protocol of four (44.4%) patients. The total treatment process was continued for 18 months. Conclusion: Management of childhood MDR-TB is a long and difficult process, but it is a preventable and treatable disease.

scholarly journals Metabolic profiling and antibacterial activity of Eryngium pristis Cham. & Schltdl. - prospecting for its use in the treatment of bacterial infections

2021 ◽  
Vol 5 (1) ◽  
pp. 020-028
Author(s):  
Fernandes Laura Silva ◽  
da Costa Ygor Ferreira Garcia ◽  
de Bessa Martha Eunice ◽  
Ferreira Adriana Lucia Pires ◽  
do Amaral Corrêa José Otávio ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Bioactive Compounds ◽  
Metabolic Profile ◽  
Bacterial Infections ◽  
Ethanolic Extract ◽  
Multidrug Resistant ◽  
Gas Chromatography Mass Spectrometry ◽  
Resistant Bacteria ◽  
Bacterial Strains ◽  
New Antibiotics

Morbidity and mortality of the infected patients by multidrug-resistant bacteria have increased, emphasizing the urgency of fight for the discovery of new innovative antibiotics. In this sense, natural products emerge as valuable sources of bioactive compounds. Among the biodiversity, Eryngium pristis Cham. & Schltdl. (Apiaceae Lindl.) is traditionally used to treat thrush and ulcers of throat and mouth, as diuretic and emmenagogue, but scarcely known as an antimicrobial agent. With this context in mind, the goals of this study were to investigate the metabolic profile and the antibacterial activity of ethanolic extract (EE-Ep) and hexane (HF-Ep), dichloromethane (DF-Ep), ethyl acetate (EAF-Ep) and butanol (BF-Ep) fractions from E. pristis leaves. Gas Chromatography-Mass Spectrometry (GC-MS) was performed to stablish the metabolic profile and revealed the presence of 12 and 14 compounds in EAF-Ep and HF-Ep, respectively. β-selinene, spathulenol, globulol, 2-methoxy-4-vinylphenol, α-amyrin, β-amyrin, and lupeol derivative were some of phytochemicals identified. The antibacterial activity was determined by Minimal Inhibitory Concentration (MIC) using the broth micro-dilution against eight ATCC® and five methicillin-resistant Staphylococcus aureus (MRSA) clinical strains. HF-Ep was the most effective (MIC ≤ 5,000 µg/µL), being active against the largest part of tested Gram-positive and Gram-negative bacterial strains, including MRSA, with exception of Escherichia coli (ATCC 25922) and Pseudomonas aeruginosa (ATCC 9027) and (ATCC 27853). These results suggest that E. pristis is a natural source of bioactive compounds for the search of new antibiotics which can be an interesting therapeutic approach to recover patients mainly infected by MRSA strains.

scholarly journals Synergistic Effect of Propidium Iodide and Small Molecule Antibiotics with the Antimicrobial Peptide Dendrimer G3KL against Gram-Negative Bacteria

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5643
Author(s):  
Bee-Ha Gan ◽  
Xingguang Cai ◽  
Sacha Javor ◽  
Thilo Köhler ◽  
Jean-Louis Reymond
Keyword(s):  
Synergistic Effect ◽  
Propidium Iodide ◽  
Synergistic Effects ◽  
Multidrug Resistant ◽  
Resistant Bacteria ◽  
Gram Negative Bacteria ◽  
Bacterial Killing ◽  
Gram Negative ◽  
Outer Membranes ◽  
New Antibiotics

There is an urgent need to develop new antibiotics against multidrug-resistant bacteria. Many antimicrobial peptides (AMPs) are active against such bacteria and often act by destabilizing membranes, a mechanism that can also be used to permeabilize bacteria to other antibiotics, resulting in synergistic effects. We recently showed that G3KL, an AMP with a multibranched dendritic topology of the peptide chain, permeabilizes the inner and outer membranes of Gram-negative bacteria including multidrug-resistant strains, leading to efficient bacterial killing. Here, we show that permeabilization of the outer and inner membranes of Pseudomonas aeruginosa by G3KL, initially detected using the DNA-binding fluorogenic dye propidium iodide (PI), also leads to a synergistic effect between G3KL and PI in this bacterium. We also identify a synergistic effect between G3KL and six different antibiotics against the Gram-negative Klebsiella pneumoniae, against which G3KL is inactive.

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