Abstract
Polymyxins are last-line antibiotics against life-threatening multidrug-resistant Gram-negative bacteria. Unfortunately, polymyxin resistance is increasingly reported, leaving a total lack of therapies. Using lipidomics and transcriptomics, we discovered that polymyxin B induced lipid A deacylation via pagL in both polymyxin-resistant and -susceptible Pseudomonas aeruginosa. Our results demonstrated that the deacylation of lipid A is an "innate immunity" response to polymyxins and a key compensatory mechanism to the aminoarabinose modification to confer high-level polymyxin resistance in P. aeruginosa. Furthermore, cutting-edge neutron reflectometry studies revealed that an assembled outer membrane (OM) with the less hydrophobic penta-acylated lipid A decreased polymyxin B penetration, compared to the hexa-acylated form. Polymyxin analogues with enhanced hydrophobicity displayed superior penetration into the tail regions of the penta-acylated lipid A OM. Our findings reveal a previously undiscovered mechanism of polymyxin resistance, wherein polymyxin-induced lipid A remodeling affects the OM packing and hydrophobicity, perturbs polymyxin penetration, and thereby confers high-level resistance.
| Original language | English |
|---|---|
| Pages (from-to) | 121-130 |
| Number of pages | 10 |
| Journal | ACS Chemical Biology |
| Volume | 13 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 19 Jan 2018 |
Cite this
}
Polymyxin-Induced Lipid A Deacylation in Pseudomonas aeruginosa Perturbs Polymyxin Penetration and Confers High-Level Resistance. / Han, Mei-Ling; Velkov, Tony; Zhu, Yan; Roberts, Kade D.; Le Brun, Anton P.; Chow, Seong Hoong; Gutu, Alina D.; Moskowitz, Samuel M.; Shen, Hsin-Hui; Li, Jian.
In: ACS Chemical Biology, Vol. 13, No. 1, 19.01.2018, p. 121-130.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Polymyxin-Induced Lipid A Deacylation in Pseudomonas aeruginosa Perturbs Polymyxin Penetration and Confers High-Level Resistance
AU - Han, Mei-Ling
AU - Velkov, Tony
AU - Zhu, Yan
AU - Roberts, Kade D.
AU - Le Brun, Anton P.
AU - Chow, Seong Hoong
AU - Gutu, Alina D.
AU - Moskowitz, Samuel M.
AU - Shen, Hsin-Hui
AU - Li, Jian
PY - 2018/1/19
Y1 - 2018/1/19
N2 - Polymyxins are last-line antibiotics against life-threatening multidrug-resistant Gram-negative bacteria. Unfortunately, polymyxin resistance is increasingly reported, leaving a total lack of therapies. Using lipidomics and transcriptomics, we discovered that polymyxin B induced lipid A deacylation via pagL in both polymyxin-resistant and -susceptible Pseudomonas aeruginosa. Our results demonstrated that the deacylation of lipid A is an "innate immunity" response to polymyxins and a key compensatory mechanism to the aminoarabinose modification to confer high-level polymyxin resistance in P. aeruginosa. Furthermore, cutting-edge neutron reflectometry studies revealed that an assembled outer membrane (OM) with the less hydrophobic penta-acylated lipid A decreased polymyxin B penetration, compared to the hexa-acylated form. Polymyxin analogues with enhanced hydrophobicity displayed superior penetration into the tail regions of the penta-acylated lipid A OM. Our findings reveal a previously undiscovered mechanism of polymyxin resistance, wherein polymyxin-induced lipid A remodeling affects the OM packing and hydrophobicity, perturbs polymyxin penetration, and thereby confers high-level resistance.
AB - Polymyxins are last-line antibiotics against life-threatening multidrug-resistant Gram-negative bacteria. Unfortunately, polymyxin resistance is increasingly reported, leaving a total lack of therapies. Using lipidomics and transcriptomics, we discovered that polymyxin B induced lipid A deacylation via pagL in both polymyxin-resistant and -susceptible Pseudomonas aeruginosa. Our results demonstrated that the deacylation of lipid A is an "innate immunity" response to polymyxins and a key compensatory mechanism to the aminoarabinose modification to confer high-level polymyxin resistance in P. aeruginosa. Furthermore, cutting-edge neutron reflectometry studies revealed that an assembled outer membrane (OM) with the less hydrophobic penta-acylated lipid A decreased polymyxin B penetration, compared to the hexa-acylated form. Polymyxin analogues with enhanced hydrophobicity displayed superior penetration into the tail regions of the penta-acylated lipid A OM. Our findings reveal a previously undiscovered mechanism of polymyxin resistance, wherein polymyxin-induced lipid A remodeling affects the OM packing and hydrophobicity, perturbs polymyxin penetration, and thereby confers high-level resistance.
UR - http://www.scopus.com/inward/record.url?scp=85040865489&partnerID=8YFLogxK
U2 - 10.1021/acschembio.7b00836
DO - 10.1021/acschembio.7b00836
M3 - Article
VL - 13
SP - 121
EP - 130
JO - ACS Chemical Biology
JF - ACS Chemical Biology
SN - 1554-8929
IS - 1
ER -