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Structure paper

TitleA new antibiotic traps lipopolysaccharide in its intermembrane transporter.
Journal, issue, pagesNature, Vol. 625, Issue 7995, Page 572-577, Year 2024
Publish dateJan 3, 2024
AuthorsKaranbir S Pahil / Morgan S A Gilman / Vadim Baidin / Thomas Clairfeuille / Patrizio Mattei / Christoph Bieniossek / Fabian Dey / Dieter Muri / Remo Baettig / Michael Lobritz / Kenneth Bradley / Andrew C Kruse / Daniel Kahne /
PubMed AbstractGram-negative bacteria are extraordinarily difficult to kill because their cytoplasmic membrane is surrounded by an outer membrane that blocks the entry of most antibiotics. The impenetrable nature ...Gram-negative bacteria are extraordinarily difficult to kill because their cytoplasmic membrane is surrounded by an outer membrane that blocks the entry of most antibiotics. The impenetrable nature of the outer membrane is due to the presence of a large, amphipathic glycolipid called lipopolysaccharide (LPS) in its outer leaflet. Assembly of the outer membrane requires transport of LPS across a protein bridge that spans from the cytoplasmic membrane to the cell surface. Maintaining outer membrane integrity is essential for bacterial cell viability, and its disruption can increase susceptibility to other antibiotics. Thus, inhibitors of the seven lipopolysaccharide transport (Lpt) proteins that form this transenvelope transporter have long been sought. A new class of antibiotics that targets the LPS transport machine in Acinetobacter was recently identified. Here, using structural, biochemical and genetic approaches, we show that these antibiotics trap a substrate-bound conformation of the LPS transporter that stalls this machine. The inhibitors accomplish this by recognizing a composite binding site made up of both the Lpt transporter and its LPS substrate. Collectively, our findings identify an unusual mechanism of lipid transport inhibition, reveal a druggable conformation of the Lpt transporter and provide the foundation for extending this class of antibiotics to other Gram-negative pathogens.
External linksNature / PubMed:38172635 / PubMed Central
MethodsEM (single particle)
Resolution3.1 - 3.8 Å
Structure data

29400

8frl

EMDB-29400, PDB-8frl:
Acinetobacter baylyi LptB2FG bound to lipopolysaccharide and a macrocyclic peptide
Method: EM (single particle) / Resolution: 3.2 Å

29401

8frm

EMDB-29401, PDB-8frm:
Acinetobacter baylyi LptB2FG bound to lipopolysaccharide.
Method: EM (single particle) / Resolution: 3.14 Å

29402

8frn

EMDB-29402: Acinetobacter baylyi LptB2FG bound to lipopolysaccharide and RG6006
PDB-8frn: Acinetobacter baylyi LptB2FG bound to lipopolysaccharide and Zosurabalpin
Method: EM (single particle) / Resolution: 3.3 Å

29403

8fro

EMDB-29403, PDB-8fro:
Acinetobacter baylyi LptB2FG bound to lipopolysaccharide and a macrocyclic peptide
Method: EM (single particle) / Resolution: 3.25 Å

29404

8frp

EMDB-29404, PDB-8frp:
Acinetobacter baylyi LptB2FGC
Method: EM (single particle) / Resolution: 3.8 Å

42206

8ufg

EMDB-42206, PDB-8ufg:
Acinetobacter baylyi LptB2FG bound to Acinetobacter baylyi lipopolysaccharide
Method: EM (single particle) / Resolution: 3.1 Å

42207

8ufh

EMDB-42207, PDB-8ufh:
Acinetobacter baylyi LptB2FG bound to Acinetobacter baylyi lipopolysaccharide and a macrocyclic peptide
Method: EM (single particle) / Resolution: 3.2 Å

Chemicals

ChemComp-Y75:
(7S,10S,13S,17P)-10-(4-aminobutyl)-7-(3-aminopropyl)-17-(6-aminopyridin-3-yl)-20-chloro-13-[(1H-indol-3-yl)methyl]-12-methyl-6,7,9,10,12,13,15,16-octahydropyrido[2,3-b][1,5,8,11,14]benzothiatetraazacycloheptadecine-8,11,14(5H)-trione

ChemComp-JSG:
(2~{R},4~{R},5~{R},6~{R})-6-[(1~{R})-1,2-bis(oxidanyl)ethyl]-2-[(2~{R},4~{R},5~{R},6~{R})-6-[(1~{R})-1,2-bis(oxidanyl)ethyl]-5-[(2~{S},3~{S},4~{R},5~{R},6~{R})-6-[(1~{S})-1,2-bis(oxidanyl)ethyl]-4-[(2~{R},3~{S},4~{R},5~{S},6~{R})-6-[(1~{S})-2-[(2~{S},3~{S},4~{S},5~{S},6~{R})-6-[(1~{S})-1,2-bis(oxidanyl)ethyl]-3,4,5-tris(oxidanyl)oxan-2-yl]oxy-1-oxidanyl-ethyl]-3,4-bis(oxidanyl)-5-phosphonooxy-oxan-2-yl]oxy-3-oxidanyl-5-phosphonooxy-oxan-2-yl]oxy-2-carboxy-2-[[(2~{R},3~{S},4~{R},5~{R},6~{R})-5-[[(3~{R})-3-dodecanoyloxytetradecanoyl]amino]-6-[[(2~{R},3~{S},4~{R},5~{R},6~{R})-3-oxidanyl-5-[[(3~{R})-3-oxidanyltetradecanoyl]amino]-4-[(3~{R})-3-oxidanyltetradecanoyl]oxy-6-phosphonooxy-oxan-2-yl]methoxy]-3-phosphonooxy-4-[(3~{R})-3-tetradecanoyloxytetradecanoyl]oxy-oxan-2-yl]methoxy]oxan-4-yl]oxy-4,5-bis(oxidanyl)oxane-2-carboxylic acid

ChemComp-LMT:
DODECYL-BETA-D-MALTOSIDE / detergent*YM

ChemComp-VB6:
Zosurabalpin

ChemComp-MG3:
(7S,10S,13S)-10-(4-aminobutyl)-7-(3-aminopropyl)-17,20-dichloro-13-[(1H-indol-3-yl)methyl]-12-methyl-6,7,9,10,12,13,15,16-octahydropyrido[2,3-b][1,5,8,11,14]benzothiatetraazacycloheptadecine-8,11,14(5H)-trione

ChemComp-WJR:
(2~{R},4~{R},5~{R},6~{R})-2-[(2~{R},4~{R},5~{R},6~{R})-5-[(2~{S},4~{R},5~{R},6~{R})-4-[(2~{R},3~{R},4~{R},5~{S},6~{S})-3-acetamido-6-carboxy-4,5-bis(oxidanyl)oxan-2-yl]oxy-6-[(1~{R})-1,2-bis(oxidanyl)ethyl]-2-carboxy-5-oxidanyl-oxan-2-yl]oxy-6-[(1~{R})-1,2-bis(oxidanyl)ethyl]-2-carboxy-2-[[(2~{R},3~{S},4~{R},5~{R},6~{R})-4-[(3~{S})-3-dodecanoyloxydodecanoyl]oxy-6-[[(2~{R},3~{S},4~{R},5~{R},6~{R})-5-[[(3~{R})-3-heptanoyloxyundecanoyl]amino]-3-oxidanyl-4-[(3~{R})-3-oxidanyloctanoyl]oxy-6-phosphonooxy-oxan-2-yl]methoxy]-5-[[(3~{S})-3-[(3~{R})-3-oxidanyldecanoyl]oxydecanoyl]amino]-3-phosphonooxy-oxan-2-yl]methoxy]oxan-4-yl]oxy-6-[(1~{R})-1,2-bis(oxidanyl)ethyl]-4,5-bis(oxidanyl)oxane-2-carboxylic acid

ChemComp-WJW:
(2~{R},4~{R},5~{R},6~{R})-2-[(2~{R},4~{R},5~{R},6~{R})-5-[(2~{S},4~{R},5~{R},6~{R})-4-[(2~{R},3~{R},4~{R},5~{S},6~{S})-3-acetamido-6-carboxy-4,5-bis(oxidanyl)oxan-2-yl]oxy-6-[(1~{R})-1,2-bis(oxidanyl)ethyl]-2-carboxy-5-oxidanyl-oxan-2-yl]oxy-6-[(1~{R})-1,2-bis(oxidanyl)ethyl]-2-carboxy-2-[[(2~{R},3~{S},4~{R},5~{R},6~{R})-4-[(3~{S})-3-dodecanoyloxydodecanoyl]oxy-6-[[(2~{R},3~{S},4~{R},5~{R},6~{R})-5-[[(3~{R})-3-heptanoyloxynonanoyl]amino]-3-oxidanyl-4-[(3~{R})-3-oxidanyloctanoyl]oxy-6-phosphonooxy-oxan-2-yl]methoxy]-5-[[(3~{S})-3-[(3~{R})-3-oxidanyldodecanoyl]oxydecanoyl]amino]-3-phosphonooxy-oxan-2-yl]methoxy]oxan-4-yl]oxy-6-[(1~{R})-1,2-bis(oxidanyl)ethyl]-4,5-bis(oxidanyl)oxane-2-carboxylic acid

Source
  • acinetobacter baylyi adp1 (bacteria)
KeywordsLIPID TRANSPORT / lipopolysaccharide / ABC / ATPase / antibiotic / macrocyclic peptide / gram-negative bacteria / ESKAPE

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