Identification of small molecules that strongly inhibit bacterial quorum sensing using a high-throughput lipid vesicle lysis assay

Polaske, Thomas J; Gahan, Curran G; Nyffeler, Kayleigh E.; Lynn, David M.; Blackwell, Helen E.

doi:10.1016/j.chembiol.2021.12.005

Cited by 6 publications

(6 citation statements)

References 61 publications

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“…Simple long chain aliphatic compounds, including tetronic acid derivatives like 3‐tetradecanoyltetronic acid (Figure 4C), have been reported to inhibit AgrC through an allosteric mechanism, though many of these compounds also inhibit bacterial growth at near‐active concentrations [84a] . Recently, our lab has reported the discovery of two small molecule agr inhibitors (10 and 11, Figure 4C) with mid‐ to high‐nanomolar potencies in cell‐based reporter assays, a potency regime rarely observed with these types of small molecules [84c] . Further evaluation of these compounds, including target elucidation, is currently underway.…”

Section: Chemical Probes Of Agrmentioning

confidence: 99%

Chemical and Biomolecular Insights into the Staphylococcus aureus Agr Quorum Sensing System: Current Progress and Ongoing Challenges

Polaske

West

Zhao

et al. 2023

Israel Journal of Chemistry

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Staphylococcus aureus is a ubiquitous bacterium that has become a major threat to human health due to its extensive toxin production and tremendous capacity for antibiotic resistance (e. g., MRSA “superbug” infections). Amid a worsening antibiotic resistance crisis, new strategies to combat this deadly microbe that remove the selective pressure of traditional approaches are in high demand. S. aureus utilizes an accessory gene regulator (agr) quorum sensing network to monitor its local cellular population and trigger a devastating communal attack, like an invading horde, once a threshold cell density has been reached. The role of the agr system in a range of disease types is still being unraveled. Herein, we discuss the present‐day biochemical understanding of agr along with unresolved details, describe its connection to the progression of infection, and review how chemical strategies have been implemented to study and intercept this signaling pathway. This research is illuminating the potential of agr as an anti‐virulence target in S. aureus and should inform the study of similar, yet less studied, agr systems in related bacterial pathogens.

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Section: Chemical Probes Of Agrmentioning

confidence: 99%

Chemical and Biomolecular Insights into the Staphylococcus aureus Agr Quorum Sensing System: Current Progress and Ongoing Challenges

Polaske

West

Zhao

et al. 2023

Israel Journal of Chemistry

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“…AHL quorum sensing does not use enzyme acylation. As quorum sensing correlates frequently with virulence, the identification of inhibitors of quorum sensing is an important objective [ 145 , 146 ]. While the favored N -acyl moiety is bacterial species-dependent (the AHL depicted in Panel B in Figure 5 is the AHL used to initiate marine Vibrio bioluminescence), the homoserine lactone ring is common to the AHL class of structures.…”

Section: Does the Marine Environment Contain β-Lactam-degrading Enzymes?mentioning

confidence: 99%

β-Lactams from the Ocean

Fisher

Mobashery

2023

Marine Drugs

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The title of this essay is as much a question as it is a statement. The discovery of the β-lactam antibiotics—including penicillins, cephalosporins, and carbapenems—as largely (if not exclusively) secondary metabolites of terrestrial fungi and bacteria, transformed modern medicine. The antibiotic β-lactams inactivate essential enzymes of bacterial cell-wall biosynthesis. Moreover, the ability of the β-lactams to function as enzyme inhibitors is of such great medical value, that inhibitors of the enzymes which degrade hydrolytically the β-lactams, the β-lactamases, have equal value. Given this privileged status for the β-lactam ring, it is therefore a disappointment that the exemplification of this ring in marine secondary metabolites is sparse. It may be that biologically active marine β-lactams are there, and simply have yet to be encountered. In this report, we posit a second explanation: that the value of the β-lactam to secure an ecological advantage in the marine environment might be compromised by its close structural similarity to the β-lactones of quorum sensing. The steric and reactivity similarities between the β-lactams and the β-lactones represent an outside-of-the-box opportunity for correlating new structures and new enzyme targets for the discovery of compelling biological activities.

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“…However, these reporter strains remain notoriously low in sensitivity, suffer from the capriciousness of living organisms, and are prone to false positives caused by failure to grow or to generate the fluorophore. Sensor liposomes have been proposed as a robust alternative for detecting membrane‐active antimicrobial peptides produced in droplets, where the antibiotic‐induced permeabilization of fluorophore‐filled liposomes generates a fluorescence signal [21,26] …”

Section: Introductionmentioning

confidence: 99%

“…Sensor liposomes have been proposed as a robust alternative for detecting membrane-active antimicrobial peptides produced in droplets, where the antibiotic-induced permeabilization of fluorophore-filled liposomes generates a fluorescence signal. [21,26] Here, we apply sensor liposomes encapsulating the selfquenching fluorescent dye calcein in microfluidic droplets to detect nonribosomal production of the membrane-active antimicrobial peptide gramicidin S (GS). Using this platform, we retrieved heterologously GS producing Escherichia coli cells from a 1 : 1000 dilution.…”

Section: Introductionmentioning

confidence: 99%

Analysing Megasynthetase Mutants at High Throughput Using Droplet Microfluidics**

Pourmasoumi,

Hengoju,

Beck

et al. 2023

ChemBioChem

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Nonribosomal peptide synthetases (NRPSs) are giant enzymatic assembly lines that deliver many pharmaceutically valuable natural products, including antibiotics. As the search for new antibiotics motivates attempts to redesign nonribosomal metabolic pathways, more robust and rapid sorting and screening platforms are needed. Here, we establish a microfluidic platform that reliably detects production of the model nonribosomal peptide gramicidin S. The detection is based on calcein‐filled sensor liposomes yielding increased fluorescence upon permeabilization. From a library of NRPS mutants, the sorting platform enriches the gramicidin S producer 14.5‐fold, decreases internal stop codons 250‐fold, and generates enrichment factors correlating with enzyme activity. Screening for NRPS activity with a reliable non‐binary sensor will enable more sophisticated structure‐activity studies and new engineering applications in the future.

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Identification of small molecules that strongly inhibit bacterial quorum sensing using a high-throughput lipid vesicle lysis assay

Cited by 6 publications

References 61 publications

Chemical and Biomolecular Insights into the Staphylococcus aureus Agr Quorum Sensing System: Current Progress and Ongoing Challenges

Chemical and Biomolecular Insights into the Staphylococcus aureus Agr Quorum Sensing System: Current Progress and Ongoing Challenges

β-Lactams from the Ocean

Analysing Megasynthetase Mutants at High Throughput Using Droplet Microfluidics**

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