6IIX

The crystal structure of acyltransferase mutant, orf11*-W163A, in complex with octanoyl-CoA

Summary for 6IIX

• Entry DOI: 10.2210/pdb6iix/pdb
• Descriptor: acyltransferase, OCTANOYL-COENZYME A, SULFATE ION, ... (4 entities in total)
• Functional Keywords: antibiotics, transferase
• Biological source: Actinoplanes teichomyceticus
• Total number of polymer chains: 1
• Total formula weight: 40175.07

Authors

Li, T.L.,Huang, C.M. (deposition date: 2018-10-08, release date: 2019-10-09, Last modification date: 2023-11-22)

Primary citation

Huang, C.M.,Lyu, S.Y.,Lin, K.H.,Chen, C.L.,Chen, M.H.,Shih, H.W.,Hsu, N.S.,Lo, I.W.,Wang, Y.L.,Li, Y.S.,Wu, C.J.,Li, T.L.
Teicoplanin Reprogrammed with the N-Acyl-Glucosamine Pharmacophore at the Penultimate Residue of Aglycone Acquires Broad-Spectrum Antimicrobial Activities Effectively Killing Gram-Positive and -Negative Pathogens.
Acs Infect Dis., 5:430-442, 2019

PubMed Abstract: Lipoglycopeptide antibiotics, for example, teicoplanin (Tei) and A40926, are more potent than vancomycin against Gram-positive (Gram-(+)) drug-resistant pathogens, for example, methicillin-resistant Staphylococcus aureus (MRSA). To extend their therapeutic effectiveness on vancomycin-resistant S. aureus (VRSA), the biosynthetic pathway of the N-acyl glucosamine (Glc) pharmacophore at residue 4 (r4) of teicoplanin pseudoaglycone redirection to residue 6 (r6) was attempted. On the basis of crystal structures, two regioselective biocatalysts Orf2*T (a triple-mutation mutant S98A/V121A/F193Y) and Orf11*S (a single-mutation mutant W163A) were engineered, allowing them to act on GlcNAc at r6. New analogs thereby made show marked antimicrobial activity against MRSA and VRSA by 2-3 orders of magnitude better than teicoplanin and vancomycin. The lipid side chain of the Tei-analogs armed with a terminal mono- or diguanidino group extends the antimicrobial specificity from Gram-(+) to Gram-negative (Gram-(-)), comparable to that of kanamycin. In addition to low cytotoxicity and high safety, the Tei analogs exhibit new modes of action as a result of resensitization of VRSA and Acinetobacter baumannii. The redirection of the biosynthetic pathway for the N-acyl-Glc pharmacophore from r4 to r6 bodes well for large-scale production of selected r6,Tei congeners in an environmentally friendly synthetic biology approach.

PubMed: 30599088
DOI: 10.1021/acsinfecdis.8b00317

Experimental method

X-RAY DIFFRACTION (1.73 Å)