5‐Benzylidene‐4‐Oxazolidinones Are Synergistic with Antibiotics for the Treatment of <i>Staphylococcus aureus</i> Biofilms

Frohock, Bram H.; Gilbertie, Jessica M.; Daiker, Jennifer C.; Schnabel, Lauren V.; Pierce, Joshua G.

doi:10.1002/cbic.201900633

Cited by 8 publications

(10 citation statements)

References 42 publications

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“…Our data are consistent with a role for TolC-mediated drug efflux in S. Typhimurium resistance to the compound. In addition to potent growth inhibition, some analogs have antibiofilm effects on S. aureus at sub-MICs as we found for S. Typhimurium (18,19). The high concentration of JJM-ox-3-70 needed to reduce S. Typhimurium biofilm makes it an unlikely candidate for development as treatment for Gram-negative biofilm-mediated infections.…”

Section: Discussionmentioning

confidence: 80%

“…In spite of their good antimicrobial efficacy against methicillinresistant strains of Staphylococcus aureus, these compounds fail to inhibit growth of Gram-negative organisms (16,17). In addition to their antimicrobial effects, some analogs have antibiofilm properties at sub-MICs (18) or can be utilized as adjuvants with existing antimicrobials (19). Understanding how the 4-oxazolidinone analogs may alter biofilm formation will allow us to create analogs with improved efficacy.…”

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confidence: 99%

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Genetic Determinants of Salmonella Resistance to the Biofilm-Inhibitory Effects of a Synthetic 4-Oxazolidinone Analog

Griewisch

Pierce

Elfenbein

2020

Appl Environ Microbiol

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Biofilms formed by Salmonella enterica are a frequent source of food supply contamination. Since biofilms are inherently resistant to disinfection, new agents capable of preventing biofilm formation are needed. Synthetic analogs of 4-oxazolidinone containing natural products have shown promise as anti-biofilm compounds against Gram-positive bacteria. The purpose of our study was twofold: to establish the anti-biofilm effects and mechanism of action of a synthetic 4-oxazolidinone analog (JJM-ox-3-70) and to establish mechanisms of resistance to this compound in Salmonella Typhimurium (STm). JJM-ox-3-70 inhibited biofilm formation but had no effect on cell growth. The anti-biofilm effects were linked to disruption of curli fimbriae and flagellar gene expression and alteration in swimming motility, suggesting an effect on multiple cellular processes. Using a 2-step screening approach of defined multi-gene and single-gene deletion mutant libraries, we identified 3 mutants that produced less biofilm in the presence of JJM-ox-3-70 than the isogenic WT with phenotypes reversed by complementation in trans. Genes responsible for STm resistance to the compound encoded acrB, a component of the major drug efflux pump AcrAB-TolC, and two genes of unknown function (STM0437 and STM1292). The results of this study suggest that JJM-ox-3-70 inhibits biofilm formation by indirect inhibition of extracellular matrix production that may be linked to disruption of flagellar motility. Further work is needed to establish the role of the newly characterized genes as potential mechanisms of biofilm intrinsic antimicrobial resistance. Importance Biofilms are resistant to killing by disinfectants and antimicrobials. Salmonella enterica biofilms facilitate long-term host colonization and persistence in food processing environments. Synthetic analogs of 4-oxazolidinone natural products show promise as anti-biofilm agents. Here, we show that a synthetic 4-oxazolidinone analog inhibits Salmonella biofilm through effects on both motility and biofilm matrix gene expression. Furthermore, we identify three genes that promote Salmonella resistance to the anti-biofilm effects of the compound. This work provides insight into the mechanism of anti-biofilm effects of a synthetic 4-oxazolidinone analog in Gram-negative bacteria and demonstrates new mechanisms of intrinsic antimicrobial resistance in Salmonella biofilms.

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Section: Discussionmentioning

confidence: 80%

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confidence: 99%

Genetic Determinants of Salmonella Resistance to the Biofilm-Inhibitory Effects of a Synthetic 4-Oxazolidinone Analog

Griewisch

Pierce

Elfenbein

2020

Appl Environ Microbiol

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“…With the ability of synoxazolidinone natural product analogues (5‐benzylidene‐4‐oxazolidinones) to disperse biofilms established, Pierce and co‐workers [137] demonstrated that related analogues, such as the formaldehyde hemiaminal of the oxazolidine core 15, work synergistically with antibiotics such as doxycycline (reducing the antibiotic's MBEC) to eradicate pre‐formed S. aureus ATCC 29213 biofilms. Subsequently, Pierce and colleagues [138] examined the activity of the 4‐oxazolidinone analogue JJM‐ox‐3‐70 (16) against the gram‐negative pathogen Salmonella typhimurium .…”

Section: ‐Oxazolidinones With Anti‐biofilm Activitymentioning

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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Section: Synoxazolidinone Natural Productsmentioning

confidence: 99%

“…During these efforts we also serendipitously prepared the formaldehyde hemiaminals of the oxazolidine core (57−59; Figure 4B) and found these compounds to have improved activity, although their lifetimes in cell culture remain unknown. 3 At this stage, we evaluated our lead compounds for their ability to eradicate preformed robust biofilms in combination with existing antibiotics. To our delight, compounds such as 59 were extremely effective at clearing biofilms and were synergistic with antibiotics such as doxycycline, reducing the antibiotics' minimal biofilm eradication concentration (MBEC) to just 16 μg/mL with only 8 μg/mL oxazolidinone 59 (Figure 4D).…”

Section: ■ Introductionmentioning

confidence: 99%

Leveraging Marine Natural Products as a Platform to Tackle Bacterial Resistance and Persistence

et al. 2021

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Conspectus Antimicrobial resistance to existing antibiotics represents one of the greatest threats to human health and is growing at an alarming rate. To further complicate treatment of bacterial infections, many chronic infections are the result of bacterial biofilms that are tolerant to treatment with antibiotics because of the presence of metabolically dormant persister cell populations. Together these threats are creating an increasing burden on the healthcare system, and a “preantibiotic” age is on the horizon if significant action is not taken by the scientific and medical communities. While the golden era of antibiotic discovery (1940s–1960s) produced most of the antibiotic classes in clinical use today, followed by several decades of limited development, there has been a resurgence in antibiotic drug discovery in recent years fueled by the academic and biotech sectors. Historically, great success has been achieved by developing next-generation variants of existing classes of antibiotics, but there remains a dire need for the identification of novel scaffolds and/or antimicrobial targets to drive future efforts to overcome resistance and tolerance. In this regard, there has been no more valuable source for the identification of antibiotics than natural products, with 69–77% of approved antibiotics either being such compounds or being derived from them. Our group has developed a program centered on the chemical synthesis and chemical microbiology of marine natural products with unusual structures and promising levels of activity against multidrug-resistant (MDR) bacterial pathogens. As we are motivated by preparing and studying the biological effects of these molecules, we are not initially pursuing a biological question but instead are allowing the observed phenotypes and activities to guide the ultimate project direction. In this Account, our recent efforts on the synoxazolidinone, lipoxazolidinone, and batzelladine natural products will be discussed and placed in the context of the field’s greatest challenges and opportunities. Specifically, the synoxazolidinone family of 4-oxazolidinone-containing natural products has led to the development of several chemical methods to prepare antimicrobial scaffolds and has revealed compounds with potent activity as adjuvants to treat bacterial biofilms. Bearing the same 4-oxazolidinone core, the lipoxazolidinones have proven to be potent single-agent antibiotics. Finally, our synthetic efforts toward the batzelladines revealed analogues with activity against a number of MDR pathogens, highlighted by non-natural stereochemical isomers with superior activity and simplified synthetic access. Taken together, these studies provide several distinct platforms for the development of novel therapeutics that can add to our arsenal of scaffolds for preclinical development and can provide insight into the biochemical processes and pathways that can be targeted by small molecules in the fight against antimicrobial-resistant and -tolerant infections. We hope that this work will s...

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5‐Benzylidene‐4‐Oxazolidinones Are Synergistic with Antibiotics for the Treatment of Staphylococcus aureus Biofilms

Cited by 8 publications

References 42 publications

Genetic Determinants of Salmonella Resistance to the Biofilm-Inhibitory Effects of a Synthetic 4-Oxazolidinone Analog

Genetic Determinants of Salmonella Resistance to the Biofilm-Inhibitory Effects of a Synthetic 4-Oxazolidinone Analog

Strategies to Improve the Potency of Oxazolidinones towards Bacterial Biofilms

Leveraging Marine Natural Products as a Platform to Tackle Bacterial Resistance and Persistence

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