Discovery of quinoline small molecules with potent dispersal activity against methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis biofilms using a scaffold hopping strategy

Abouelhassan, Yasmeen; Garrison, Aaron T.; Burch, Gena M.; Wong, Wilson; Norwood, Verrill M.; Huigens, Robert W.

doi:10.1016/j.bmcl.2014.09.009

Cited by 66 publications

(45 citation statements)

References 22 publications

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“…Using a “scaffold-hopping” approach, Huigens sought to divert the success of the bromophenazine work to a simplified quinoline scaffold, generating a library of small molecules with comparable activities to the phenazine analogs, some of which were potent biofilm inhibitors. 246,247 …”

Section: Targeting Quorum Sensing and Bacterial Signalingmentioning

confidence: 99%

Natural Products as Platforms To Overcome Antibiotic Resistance

2017

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Natural products have served as powerful therapeutics against pathogenic bacteria since the golden age of antibiotics of the mid-20th century. However, the increasing frequency of antibiotic-resistant infections clearly demonstrates that new antibiotics are critical for modern medicine. Because combinatorial approaches have not yielded effective drugs, we propose that the development of new antibiotics around proven natural scaffolds is the best short-term solution to the rising crisis of antibiotic resistance. We analyze herein synthetic approaches aiming to reengineer natural products into potent antibiotics. Furthermore, we discuss approaches in modulating quorum sensing and biofilm formation as a nonlethal method, as well as narrowspectrum pathogen-specific antibiotics, which are of interest given new insights into the implications of disrupting the microbiome.

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Section: Targeting Quorum Sensing and Bacterial Signalingmentioning

confidence: 99%

Natural Products as Platforms To Overcome Antibiotic Resistance

2017

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“…Our work relatedt op henazine antibiotics has led to the identification of as eries of halogenated phenazine small molecules that demonstrate potent biofilm-eradicating activities against multiple Gram-positive bacteria, includingM RSA, MRSE and VRE. The modular chemical syntheses that have been employed during these studies have been critical in establishing activity profiles and structure-activity relationshipsf or halogenatedp henazine antibacterial agents;h owever,a dditional synthesis efforts are ongoing and will be reported in due course.W eh ave utilized the halogenatedp henazinea sinspiration to scaffoldh op to an extensive parallel library of halogenated quinoline biofilm-eradicating agents, [136][137][138][139][140] which were not presented in this review,b ut enhance the translational potential of these compounds. HP-14 has been av aluablet ool molecule for establishing the mode of action of HP biofilmeradicating agentsw hile defining criticali ron acquisition targets and pathways involved in MRSA biofilm survival.…”

Section: Future Perspectives and Conclusionmentioning

confidence: 99%

Phenazine Antibiotic‐Inspired Discovery of Bacterial Biofilm‐Eradicating Agents

2019

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Bacterial biofilms are surface‐attached communities of slow‐growing and non‐replicating persister cells that demonstrate high levels of antibiotic tolerance. Biofilms occur in nearly 80 % of infections and present unique challenges to our current arsenal of antibiotic therapies, all of which were initially discovered for their abilities to target rapidly dividing, free‐floating planktonic bacteria. Bacterial biofilms are credited as the underlying cause of chronic and recurring bacterial infections. Innovative approaches are required to identify new small molecules that operate through bacterial growth‐independent mechanisms to effectively eradicate biofilms. One source of inspiration comes from within the lungs of young cystic fibrosis (CF) patients, who often endure persistent Staphylococcus aureus infections. As these CF patients age, Pseudomonas aeruginosa co‐infects the lungs and utilizes phenazine antibiotics to eradicate the established S. aureus infection. Our group has taken a special interest in this microbial competition strategy and we are investigating the potential of phenazine antibiotic‐inspired compounds and synthetic analogues thereof to eradicate persistent bacterial biofilms. To discover new biofilm‐eradicating agents, we have established an interdisciplinary research program involving synthetic medicinal chemistry, microbiology and molecular biology. From these efforts, we have identified a series of halogenated phenazines (HPs) that potently eradicate bacterial biofilms, and future work aims to translate these preliminary findings into ground‐breaking clinical advances for the treatment of persistent biofilm infections.

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“…8-hydroxyquinoline (HQ) is a well-studied, privileged structure, with activity against a wide range of cell types (Prachayasittikul, Prachayasittikul, Ruchirawat, & Prachayasittikul, 2013;Song, Xu, Chen, Zhan, & Liu, 2015), including anticancer activity (Barilli et al, 2014;Bhat, Shim, Zhang, Chong, & Liu, 2012;Chang, Chen, Wang, Tzeng, & Chen, 2010;Feng et al, 2015;Li et al, 2016;Moret et al, 2009;Mrozek-Wilczkiewicz et al, 2015;Sosi c et al, 2013;Spaczy nska, Tabak, Malarz, & Musiol, 2014), antifungal activity (Cieslik et al, 2012;Musiol et al, 2006), and antibacterial activity (Warner, Musto, Turesky, & Soloway, 1975). The HQ are active against several bacterial species including Staphylococcus aureus and Staphylococcus epidermidis (Abouelhassan et al, 2014(Abouelhassan et al, , 2015Basak et al, 2016;Garrison et al, 2017;Lam et al, 2014), Enterococcus faecium (Basak et al, 2016;Garrison et al, 2017), Burkholderia pseudomallei (Wangtrakuldee et al, 2013), Neisseria gonorrhoeae, (Lawung et al, 2018), Listeria monocytogenes (Cherdtrakulkiat et al, 2016), and Mycobacterium avium (Hongmanee, Rukseree, Buabut, Somsri, & Palittapongarnpim, 2007;Kos et al, 2015). In addition, activity of the HQ compounds against replicating and nonreplicating Mycobacterium tuberculosis has been demonstrated in medium containing copper and in infected guinea pigs (Ananthan et al, 2009;Darby & Nathan, 2010;Hongmanee et al, 2007;Shah et al, 2016;Tison, 1952;…”

Section: Introductionmentioning

confidence: 99%

8‐Hydroxyquinolines are bactericidal against Mycobacterium tuberculosis

Odingo

Early

Smith

et al. 2019

Drug Development Research

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There is an urgent need for new treatments effective against Mycobacterium tuberculosis, the causative agent of tuberculosis. The 8‐hydroxyquinoline series is a privileged scaffold with anticancer, antifungal, and antibacterial activities. We conducted a structure–activity relationship study of the series regarding its antitubercular activity using 26 analogs. The 8‐hydroxyquinolines showed good activity against M. tuberculosis, with minimum inhibitory concentrations (MIC90) of <5 μM for some analogs. Small substitutions at C5 resulted in the most potent activity. Substitutions at C2 generally decreased potency, although a sub‐family of 2‐styryl‐substituted analogs retained activity. Representative compounds demonstrated bactericidal activity against replicating M. tuberculosis with >4 log kill at 10× MIC over 14 days. The majority of the compounds demonstrated cytotoxicity (IC50 of <100 μM). Further development of this series as antitubercular agents should address the cytotoxicity liability. However, the 8‐hydroxyquinoline series represents a useful tool for chemical genomics to identify novel targets in M. tuberculosis.

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Discovery of quinoline small molecules with potent dispersal activity against methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis biofilms using a scaffold hopping strategy

Cited by 66 publications

References 22 publications

Natural Products as Platforms To Overcome Antibiotic Resistance

Natural Products as Platforms To Overcome Antibiotic Resistance

Phenazine Antibiotic‐Inspired Discovery of Bacterial Biofilm‐Eradicating Agents

8‐Hydroxyquinolines are bactericidal against Mycobacterium tuberculosis

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