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Dr. Sebastian Hiller - The outer membrane insertase as a target for novel antibiotics

 

Sebastian Hiller

Biozentrum, University of Basel, Basel, Switzerland

The outer membrane insertase as a target for novel antibiotics

The outer membrane insertase complex BAM of Gram-negative bacteria is a potentially attractive target to novel antibiotic. This is due to its location at the cellular periphery, which prevents many of the common bacterial defense strategies. BAM receives its substrates – unfolded outer membrane proteins – from a chain of periplasmic chaperones to fold and insert them into the membrane. BAM lacks a classical catalytic center and for long time, it had remained questionable whether BAM can be inhibited at all.

I will describe how an integrated structural biology approach has allowed us to resolve key functional mechanisms involved in outer membrane protein biogenesis and to validate BAM as the direct target for two recently discovered novel antibiotics [1,2]. In particular, the development of conformation-selective nanobodies against BAM provided the technical means to resolve the conformational ensemble of the central subunit BamA by NMR spectroscopy [3,4]. By combining NMR spectroscopy, cryo-electron microscopy, X-ray crystallography, native mass spectrometry, molecular dynamics simulation, biophysical measurements and an in vivo infection model, we could resolve at atomic level how each of the antibiotics darobactin and OMPTAinhibits the BAM complex [5,6]. Remarkably, the data identify the existence of two functional hotspots in the BAM complex that are fundamentally different. BAM is thus established as a true bacterial Achilles heel.

Selected references

  1. A. Luther, M. Urfer, et al., Nature 576, 452–458 (2019)
  2. Y. Imai, K.J. Meyer, et al. Nature 576, 459–464 (2019)
  3. J.B. Hartmann et al., J. Am. Chem. Soc. 140, 11252–11260 (2018)
  4. H. Kaur, J.B. Hartmann, R.P. Jakob, M. Zahn et al. J. Biomol. NMR 73, 375–384 (2019)
  5. H. Kaur, R.P. Jakob et al., Nature 593, 125–129 (2021)
  6. Unpublished work

Contact: Jérome Nigou (Jerome.Nigou@ipbs.fr)
Link to attend the seminar: https://meet.starleaf.com/4830740721/app

17 May

11:00 - 12:00

Seminar room - IPBS | Hybrid conference