Isothiazolone–Nitroxide Hybrids with Activity against Antibiotic-Resistant <i>Staphylococcus aureus</i> Biofilms

Verderosa, Anthony D.; Hawas, Sophia; Harris, Jessica; Totsika, Makrina; Fairfull‐Smith, Kathryn E.

doi:10.1021/acsomega.1c06433

Cited by 12 publications

(11 citation statements)

References 52 publications

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“…However, oxazolidinone-nitroxide hybrid 11 showed a >2-fold reduction in MBEC value compared to linezolid on MRSA biofilms (Table ), suggesting moderately improved biofilm eradication activity against MRSA in vitro . Our previous work investigated the treatment of isothiazolone-nitroxide hybrids on S. aureus biofilms . We reported an MBEC-99.9% (the concentration required to kill 99.9% of the biofilm) of 35 μM for MSSA ATCC 29213 (an 8-fold increase in comparison to the parent isothiazolone compound) and 280 μM MRSA ATCC 33591 (equivalent to the parent isothiazolone compound).…”

Section: Resultsmentioning

confidence: 99%

“… Specific fatty acids suppress the expression of genes that regulate quorum sensing to control biofilm formation . Ciprofloxacin has also been conjugated with other biofilm disruptors such as nitroxides ( 4 , Figure ), − antimicrobial peptides, and antioxidants ( 5 , Figure ) , to improve the potency of antibiotics. We hypothesized that functionalizing linezolid 1 with a biofilm dispersing agent, such as a nitroxide, may improve its potency by increasing its antibiofilm activity and minimizing the development of resistance, thereby extending its useful lifetime as an important last resort antibiotic.…”

Section: Introductionmentioning

confidence: 99%

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Simple and Efficient Synthesis of 3-Aryl-2-oxazolidinone Scaffolds Enabling Increased Potency toward Biofilms

et al. 2023

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Infectious diseases caused by bacterial pathogens are a leading cause of mortality worldwide. In particular, recalcitrant bacterial communities known as biofilms are implicated in persistent and difficult to treat infections. With a diminishing antibiotic pipeline, new treatments are urgently required to combat biofilm infections. An emerging strategy to develop new treatments is the hybridization of antibiotics. The benefit of this approach is the extension of the useful lifetime of existing antibiotics. The oxazolidinones, which include the last resort antibiotic linezolid, are an attractive target for improving antibiofilm efficacy as they present one of the most recently discovered classes of antibiotics. A key step in the synthesis of new 3-aryl-2-oxazolidinone derivatives is the challenging formation of the oxazolidinone ring. Herein we report a direct synthetic route to the piperazinyl functionalized 3-aryl-2-oxazolidinone 17. We also demonstrate an application of these piperazine molecules by functionalizing them with a nitroxide moiety as a strategy to extend the useful lifetime of oxazolidinones and improve their potency against Methicillin-resistant Staphylococcus aureus (MRSA) biofilms. The antimicrobial susceptibility of the linezolid-nitroxide conjugate 11 and its corresponding methoxyamine derivative 12 (a control for biofilm dispersal) was assessed against planktonic cells and biofilms of MRSA. In comparison to linezolid and our lead compound 10 (a piperazinyl oxazolidinone derivative), the linezolid-nitroxide conjugate 11 displayed a minimum inhibitory concentration that was 4–16-fold higher. The opposite effect was seen in biofilms where the linezolid-nitroxide hybrid 11 was >2-fold more effective (160 μg/mL versus >320 μg/mL) in eradicating MRSA biofilms. The methoxyamine derivative 12 performed on par with linezolid. The drug-likeness of the compounds was also assessed, and all compounds were predicted to have good oral bioavailability. Our piperazinyl oxazolidinone derivative 10 was confirmed to be lead-like and would be a good lead candidate for future functionalized oxazolidinones. The modification of antibiotics with a dispersal agent appears to be a promising approach for eradicating MRSA biofilms and overcoming the antibiotic resistance associated with the biofilm mode of growth.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Simple and Efficient Synthesis of 3-Aryl-2-oxazolidinone Scaffolds Enabling Increased Potency toward Biofilms

et al. 2023

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“…24 Anthony Verderosa (University of Queensland, Australia) described the approach of combining two pharmacophores into a hybrid form, particularly with synthesizing new antibiotics to help combat antimicrobial resistance. 25,26 A library of known antibiotics with a functionalized azide handle was used to form hybrids, and it was showcased that a vancomycin hybrid was obtained that is >100-fold more potent in antibiotic-resistant strains MRSA, VRSA, and VRE. In addition, an ocatpeptin hybrid was synthesized that is >60 fold more active in polymyxin-resistant Acinetobacter baumannii, and another ocatpeptin hybrid was found to be >4 fold more potent in MDR Klebsiella pneumoniae.…”

Section: ■ Daymentioning

confidence: 99%

“…Overall, this hybrid platform may result in fast-tracked drug candidates and buy more time until brand new antibiotic structures are discovered. 25,26 Neil Kad (University of Kent, UK) mentioned that infections are the second leading cause of cancer patient deaths and that, in the UK, 20 hospital admissions per month are from individuals with cancer who have an infection. Neil shared his work on developing new adjuvant antimicrobials tailored for patients undergoing cancer chemotherapy with the hope of decreasing infection-related deaths.…”

Section: ■ Daymentioning

confidence: 99%

Meeting Proceedings from ICBS 2022 – Uncovering Solutions for Diseases

Syphers,

Xue,

et al. 2023

ACS Chem. Biol.

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ICBS 2022 was a refreshing multi-day event where it was justified that the advancement of chemical biology did not halt due to the pandemic, but in contrast, amazing findings were discovered within the restrictions of the SARS-CoV-2 pandemic. All aspects of this annual gathering reinforced that interconnecting the branches of chemical biology through collaboration, the sharing of ideas and knowledge, and networking are enabling the discovery and diversification of applications that will arm scientists of this world in "uncovering solutions for diseases."

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“…A range of approaches to target biofilms are in development such as hybrid drugs, [39][40][41][42][43] antimicrobial peptides, [44][45][46][47] and quaternary ammonium compounds. [28,[48][49][50] Current clinical treatment of biofilm infections still largely relies on antibiotics.…”

Section: The Oxazolidinone Class Of Antibioticsmentioning

confidence: 99%

Strategies to Improve the Potency of Oxazolidinones towards Bacterial Biofilms

Ndukwe

Wiedbrauk

Boase

et al. 2022

Chemistry An Asian Journal

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Biofilms are part of the natural lifecycle of bacteria and are known to cause chronic infections that are difficult to treat. Most antibiotics are developed and tested against bacteria in the planktonic state and are ineffective against bacterial biofilms. The oxazolidinones, including the last resort drug linezolid, are one of the main classes of synthetic antibiotics progressed to clinical use in the last 50 years. They have a unique mechanism of action and only develop low levels of resistance in the clinical setting. With the aim of providing insight into strategies to design more potent antibiotic compounds with activity against bacterial biofilms, we review the biofilm activity of clinically approved oxazolidinones and report on structural modifications to oxazolidinones and their delivery systems which lead to enhanced anti‐biofilm activity.

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Isothiazolone–Nitroxide Hybrids with Activity against Antibiotic-Resistant Staphylococcus aureus Biofilms

Cited by 12 publications

References 52 publications

Simple and Efficient Synthesis of 3-Aryl-2-oxazolidinone Scaffolds Enabling Increased Potency toward Biofilms

Simple and Efficient Synthesis of 3-Aryl-2-oxazolidinone Scaffolds Enabling Increased Potency toward Biofilms

Meeting Proceedings from ICBS 2022 – Uncovering Solutions for Diseases

Strategies to Improve the Potency of Oxazolidinones towards Bacterial Biofilms

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