Increasing the permeability of Escherichia coli using MAC13243

Muheim, Claudio; Götzke, Hansjörg; Eriksson, Anna; Lindberg, Stina; Lauritsen, Ida; Nørholm, Morten H. H.; Daley, Daniel O.

doi:10.1038/s41598-017-17772-6

Cited by 103 publications

(100 citation statements)

References 57 publications

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“…The authors of that study showed that this molecule makes cells more susceptible to bulky antibiotics, like vancomycin, that are normally excluded by the outer membrane. Given the prior connection of MAC13243 with LolA (26), it was concluded that the permeability defect induced by the compound was a result of its interference with the lipoprotein transport pathway (38). However, based on our analysis described above, we reasoned that the observed effect of MAC13243 was more likely to result from its breakdown product inhibiting the Rod system.…”

Section: Relationship Between Mic and Mecillinam Suppression Activitymentioning

confidence: 86%

“…Rod system inactivation results in an outer membrane permeability defect. MAC13243 was also recently identified in a high-throughput screen for molecules that disrupt the outer membrane permeability barrier of E. coli (38). The authors of that study showed that this molecule makes cells more susceptible to bulky antibiotics, like vancomycin, that are normally excluded by the outer membrane.…”

Section: Relationship Between Mic and Mecillinam Suppression Activitymentioning

confidence: 99%

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Pathway-Directed Screen for Inhibitors of the Bacterial Cell Elongation Machinery

Buss

Baidin

Welsh

et al. 2019

Antimicrob Agents Chemother

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New antibiotics are needed to combat the growing problem of resistant bacterial infections. An attractive avenue toward the discovery of such next-generation therapies is to identify novel inhibitors of clinically validated targets, like cell wall biogenesis. We have therefore developed a pathway-directed whole-cell screen for small molecules that block the activity of the Rod system of Escherichia coli. This conserved multiprotein complex is required for cell elongation and the morphogenesis of rod-shaped bacteria. It is composed of cell wall synthases and membrane proteins of unknown function that are organized by filaments of the actin-like MreB protein. Our screen takes advantage of the conditional essentiality of the Rod system and the ability of the beta-lactam mecillinam (also known as amdinocillin) to cause a toxic malfunctioning of the machinery. Rod system inhibitors can therefore be identified as molecules that promote growth in the presence of mecillinam under conditions permissive for the growth of Rod– cells. A screen of ∼690,000 compounds identified 1,300 compounds that were active against E. coli. Pathway-directed screening of a majority of this subset of compounds for Rod inhibitors successfully identified eight analogs of the MreB antagonist A22. Further characterization of the A22 analogs identified showed that their antibiotic activity under conditions where the Rod system is essential was strongly correlated with their ability to suppress mecillinam toxicity. This result combined with those from additional biological studies reinforce the notion that A22-like molecules are relatively specific for MreB and suggest that the lipoprotein transport factor LolA is unlikely to be a physiologically relevant target as previously proposed.

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Section: Relationship Between Mic and Mecillinam Suppression Activitymentioning

confidence: 86%

Section: Relationship Between Mic and Mecillinam Suppression Activitymentioning

confidence: 99%

Pathway-Directed Screen for Inhibitors of the Bacterial Cell Elongation Machinery

Buss

Baidin

Welsh

et al. 2019

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…An independent screen illustrated that MAC13243 treatment caused increased cellular permeability in E. coli, which also occurs when LolA levels are depleted [131]. MAC13243 and A22 were suggested to act on LolA to permeabilize the OM.…”

Section: Inhibiting Lipoprotein Transportmentioning

confidence: 99%

Countering Gram-Negative Antibiotic Resistance: Recent Progress in Disrupting the Outer Membrane with Novel Therapeutics

Lehman

Grabowicz

2019

Antibiotics

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Gram-negative bacteria shield themselves from antibiotics by producing an outer membrane (OM) that forms a formidable permeability barrier. Multidrug resistance among these organisms is a particularly acute problem that is exacerbated by the OM. The poor penetrance of many available antibiotics prevents their clinical use, and efforts to discover novel classes of antibiotics against Gram-negative bacteria have been unsuccessful for almost 50 years. Recent insights into how the OM is built offer new hope. Several essential multiprotein molecular machines (Bam, Lpt, and Lol) work in concert to assemble the barrier and offer a swathe of new targets for novel therapeutic development. Murepavadin has been at the vanguard of these efforts, but its recently reported phase III clinical trial toxicity has tempered the anticipation of imminent new clinical options. Nonetheless, the many concerted efforts aimed at breaking down the OM barrier provide a source of ongoing optimism for what may soon come through the development pipeline. We will review the current state of drug development against the OM assembly targets, highlighting insightful new discovery approaches and strategies.

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“…To this extent, a high-throughput analysis revealed the small molecule MAC13243 as membrane permeabiliser to facilitate increased influx of large antibiotics in E. coli. This molecule was identified as an inhibitor of the LolA, a periplasmic chaperone that traffics lipoproteins from the inner to the OM [103].…”

Section: Om Permeabilisersmentioning

confidence: 99%

Reversing resistance to counter antimicrobial resistance in the World Health Organisation’s critical priority of most dangerous pathogens

Venter

2019

Bioscience Reports

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The speed at which bacteria develop antimicrobial resistance far outpace drug discovery and development efforts resulting in untreatable infections. The World Health Organisation recently released a list of pathogens in urgent need for the development of new antimicrobials. The organisms that are listed as the most critical priority are all Gram-negative bacteria resistant to the carbapenem class of antibiotics. Carbapenem resistance in these organisms is typified by intrinsic resistance due to the expression of antibiotic efflux pumps and the permeability barrier presented by the outer membrane, as well as by acquired resistance due to the acquisition of enzymes able to degrade β-lactam antibiotics. In this perspective article we argue the case for reversing resistance by targeting these resistance mechanisms – to increase our arsenal of available antibiotics and drastically reduce antibiotic discovery times – as the most effective way to combat antimicrobial resistance in these high priority pathogens.

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Increasing the permeability of Escherichia coli using MAC13243

Cited by 103 publications

References 57 publications

Pathway-Directed Screen for Inhibitors of the Bacterial Cell Elongation Machinery

Pathway-Directed Screen for Inhibitors of the Bacterial Cell Elongation Machinery

Countering Gram-Negative Antibiotic Resistance: Recent Progress in Disrupting the Outer Membrane with Novel Therapeutics

Reversing resistance to counter antimicrobial resistance in the World Health Organisation’s critical priority of most dangerous pathogens

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