Structural basis of ligand-selective transcriptional activation in the MerR-family antibiotic resistance regulator AlbA
- 1King's College London
Abstract
Multidrug-resistant pathogens demand novel resistance-breaking strategies. The oligoarylamide albicidin and pyrrolobenzodiazepines (PBDs) are potent antibacterials with unrelated scaffolds, yet both are neutralized by albA gene products in many Gram-negatives: AlbA, an albicidin-responsive self-upregulating MerR-family factor, and the smaller AlbAS, its unique ligand binding domain (LBD) alone. How AlbA couples ligand sensing to transcriptional activation has remained elusive. Here, using an integrative multidisciplinary approach, we define this mechanism and show that albicidin and PBDs elicit different responses. Crystal structures reveal C8-linked PBDs bound to AlbAS at the N- and C-terminal subdomains (NTD, CTD) of the central tunnel in poses dictated by C8-tail chemistry. This plasticity sequesters diverse PBDs with nanomolar affinities. Cryo-EM shows AlbA as an autoinhibited dimer in which a reciprocal arm closes the NTD end of the partner's tunnel, restricting PBD binding to the CTD while the DNA binding domains (DBDs) are mobile. Albicidin binding is incompatible with this arrangement, whereas PBDs, as CTD plugs, do not perturb the native equilibrium between autoinhibited and promoter-competent states. We visualized the latter by cryo-EM in the RNAP-DNA-AlbA complex. By blocking albicidin-mediated enhancement in vitro, PBDs act as resistance-breaking partners for albicidin and a route to overcoming albA-dependent resistance to oligoarylamide antibiotics.
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BibTeX
@misc{palma2026structural,
title = {{Structural basis of ligand-selective transcriptional activation in the MerR-family antibiotic resistance regulator AlbA}},
author = {M. Di Palma and A. Grinzato and P. Andriollo and L. Kleebauer and M. Leusciatti and G. Morra and J. M. Sutton and K. M. Rahman and R. A. Steiner},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.21.753095},
url = {https://www.biorxiv.org/content/10.64898/2026.09.21.753095v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Structural basis of ligand-selective transcriptional activation in the MerR-family antibiotic resistance regulator AlbA
AU - M. Di Palma
AU - A. Grinzato
AU - P. Andriollo
AU - L. Kleebauer
AU - M. Leusciatti
AU - G. Morra
AU - J. M. Sutton
AU - K. M. Rahman
AU - R. A. Steiner
PY - 2026
DA - 2026/09/21
PB - bioRxiv
DO - 10.64898/2026.09.21.753095
UR - https://www.biorxiv.org/content/10.64898/2026.09.21.753095v1
AB - Multidrug-resistant pathogens demand novel resistance-breaking strategies. The oligoarylamide albicidin and pyrrolobenzodiazepines (PBDs) are potent antibacterials with unrelated scaffolds, yet both are neutralized by albA gene products in many Gram-negatives: AlbA, an albicidin-responsive self-upregulating MerR-family factor, and the smaller AlbAS, its unique ligand binding domain (LBD) alone. How AlbA couples ligand sensing to transcriptional activation has remained elusive. Here, using an integrative multidisciplinary approach, we define this mechanism and show that albicidin and PBDs elicit different responses. Crystal structures reveal C8-linked PBDs bound to AlbAS at the N- and C-terminal subdomains (NTD, CTD) of the central tunnel in poses dictated by C8-tail chemistry. This plasticity sequesters diverse PBDs with nanomolar affinities. Cryo-EM shows AlbA as an autoinhibited dimer in which a reciprocal arm closes the NTD end of the partner's tunnel, restricting PBD binding to the CTD while the DNA binding domains (DBDs) are mobile. Albicidin binding is incompatible with this arrangement, whereas PBDs, as CTD plugs, do not perturb the native equilibrium between autoinhibited and promoter-competent states. We visualized the latter by cryo-EM in the RNAP-DNA-AlbA complex. By blocking albicidin-mediated enhancement in vitro, PBDs act as resistance-breaking partners for albicidin and a route to overcoming albA-dependent resistance to oligoarylamide antibiotics.
ER -