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Adaptation of a Bacterial Multidrug Resistance System Revealed by the Structure and Function of AlbA.

Sikandar A, Cirnski K, Testolin G, Volz C, Brönstrup M, Kalinina OV, Müller R, Koehnke J
J Am Chem Soc 140 16641-16649 (2018)
Related entries: 6h95, 6h96, 6hai

Cited: 10 times
EuropePMC logo PMID: 30422653

Abstract

To combat the rise of antimicrobial resistance, the discovery of new antibiotics is paramount. Albicidin and cystobactamid are related natural product antibiotics with potent activity against Gram-positive and, crucially, Gram-negative pathogens. AlbA has been reported to neutralize albicidin by binding it with nanomolar affinity. To understand this potential resistance mechanism, we determined structures of AlbA and its complex with albicidin. The structures revealed AlbA to be comprised of two domains, each unexpectedly resembling the multiantibiotic neutralizing protein TipA. Binding of the long albicidin molecule was shared pseudosymmetrically between the two domains. The structure also revealed an unexpected chemical modification of albicidin, which we demonstrate to be promoted by AlbA, and to reduce albicidin potency; we propose a mechanism for this reaction. Overall, our findings suggest that AlbA arose through internal duplication in an ancient TipA-like gene, leading to a new binding scaffold adapted to the sequestration of long-chain antibiotics.

Reviews citing this publication (2)

  1. Exploring antibiotic resistance with chemical tools. Velema WA. Chem Commun (Camb) 59 6148-6158 (2023)
  2. Newly Discovered Mechanisms of Antibiotic Self-Resistance with Multiple Enzymes Acting at Different Locations and Stages. Chen X, Pan HX, Tang GL. Antibiotics (Basel) 12 35 (2022)

Articles citing this publication (8)

  1. A Specialized Polythioamide-Binding Protein Confers Antibiotic Self-Resistance in Anaerobic Bacteria. Gude F, Molloy EM, Horch T, Dell M, Dunbar KL, Krabbe J, Groll M, Hertweck C. Angew Chem Int Ed Engl 61 e202206168 (2022)
  2. Optical Modulation of Antibiotic Resistance by Photoswitchable Cystobactamids. Testolin G, Richter J, Ritter A, Prochnow H, Köhnke J, Brönstrup M. Chemistry 28 e202201297 (2022)
  3. 2D Graphdiyne Oxide Serves as a Superior New Generation of Antibacterial Agents. Zhang Y, Liu W, Li Y, Yang YW, Dong A, Li Y. iScience 19 662-675 (2019)
  4. Antibiotic binding releases autoinhibition of the TipA multidrug-resistance transcriptional regulator. Jiang X, Zhang L, Teng M, Li X. J Biol Chem 295 17865-17876 (2020)
  5. Improvement of the antimicrobial potency, pharmacokinetic and pharmacodynamic properties of albicidin by incorporation of nitrogen atoms. Zborovsky L, Kleebauer L, Seidel M, Kostenko A, von Eckardstein L, Gombert FO, Weston J, Süssmuth RD. Chem Sci 12 14606-14617 (2021)
  6. Molecular mechanism of topoisomerase poisoning by the peptide antibiotic albicidin. Michalczyk E, Hommernick K, Behroz I, Kulike M, Pakosz-Stępień Z, Mazurek L, Seidel M, Kunert M, Santos K, von Moeller H, Loll B, Weston JB, Mainz A, Heddle JG, Süssmuth RD, Ghilarov D. Nat Catal 6 52-67 (2023)
  7. Reductive inactivation of the hemiaminal pharmacophore for resistance against tetrahydroisoquinoline antibiotics. Wen WH, Zhang Y, Zhang YY, Yu Q, Jiang CC, Tang MC, Pu JY, Wu L, Zhao YL, Shi T, Zhou J, Tang GL. Nat Commun 12 7085 (2021)
  8. Transcription activation by the resistance protein AlbA as a tool to evaluate derivatives of the antibiotic albicidin. Kosol S, Rostock L, Barsig J, Tabarelli T, Hommernick K, Kulike M, Eulberg T, Seidel M, Behroz I, Kleebauer L, Grätz S, Mainz A, Süssmuth RD. Chem Sci 14 5069-5078 (2023)


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