TY - JOUR
T1 - Insights into Acinetobacter baumannii fatty acid synthesis 3-oxoacyl-ACP reductases
AU - Cross, Emily M.
AU - Adams, Felise G.
AU - Waters, Jack K.
AU - Aragão, David
AU - Eijkelkamp, Bart A.
AU - Forwood, Jade K.
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Treatments
for ‘superbug’ infections are the focus for innovative research, as drug
resistance threatens human health and medical practices globally. In
particular, Acinetobacter baumannii (Ab) infections are
repeatedly reported as difficult to treat due to increasing antibiotic
resistance. Therefore, there is increasing need to identify novel
targets in the development of different antimicrobials. Of particular
interest is fatty acid synthesis, vital for the formation of
phospholipids, lipopolysaccharides/lipooligosaccharides, and
lipoproteins of Gram-negative envelopes. The bacterial type II fatty
acid synthesis (FASII) pathway is an attractive target for the
development of inhibitors and is particularly favourable due to the
differences from mammalian type I fatty acid synthesis. Discrete enzymes
in this pathway include two reductase enzymes: 3-oxoacyl-acyl carrier
protein (ACP) reductase (FabG) and enoyl-ACP reductase (FabI). Here, we
investigate annotated FabG homologs, finding a low-molecular weight
3-oxoacyl-ACP reductase, as the most likely FASII FabG candidate, and
high-molecular weight 3-oxoacyl-ACP reductase (HMwFabG), showing
differences in structure and coenzyme preference. To date, this is the
second bacterial high-molecular weight FabG structurally characterized,
following FabG4 from Mycobacterium. We show that ΔAbHMwfabG
is impaired for growth in nutrient rich media and pellicle formation.
We also modelled a third 3-oxoacyl-ACP reductase, which we annotated as AbSDR.
Despite containing residues for catalysis and the ACP coordinating
motif, biochemical analyses showed limited activity against an
acetoacetyl-CoA substrate in vitro. Inhibitors designed to target FabG
proteins and thus prevent fatty acid synthesis may provide a platform
for use against multidrug-resistant pathogens including A. baumannii.
AB - Treatments
for ‘superbug’ infections are the focus for innovative research, as drug
resistance threatens human health and medical practices globally. In
particular, Acinetobacter baumannii (Ab) infections are
repeatedly reported as difficult to treat due to increasing antibiotic
resistance. Therefore, there is increasing need to identify novel
targets in the development of different antimicrobials. Of particular
interest is fatty acid synthesis, vital for the formation of
phospholipids, lipopolysaccharides/lipooligosaccharides, and
lipoproteins of Gram-negative envelopes. The bacterial type II fatty
acid synthesis (FASII) pathway is an attractive target for the
development of inhibitors and is particularly favourable due to the
differences from mammalian type I fatty acid synthesis. Discrete enzymes
in this pathway include two reductase enzymes: 3-oxoacyl-acyl carrier
protein (ACP) reductase (FabG) and enoyl-ACP reductase (FabI). Here, we
investigate annotated FabG homologs, finding a low-molecular weight
3-oxoacyl-ACP reductase, as the most likely FASII FabG candidate, and
high-molecular weight 3-oxoacyl-ACP reductase (HMwFabG), showing
differences in structure and coenzyme preference. To date, this is the
second bacterial high-molecular weight FabG structurally characterized,
following FabG4 from Mycobacterium. We show that ΔAbHMwfabG
is impaired for growth in nutrient rich media and pellicle formation.
We also modelled a third 3-oxoacyl-ACP reductase, which we annotated as AbSDR.
Despite containing residues for catalysis and the ACP coordinating
motif, biochemical analyses showed limited activity against an
acetoacetyl-CoA substrate in vitro. Inhibitors designed to target FabG
proteins and thus prevent fatty acid synthesis may provide a platform
for use against multidrug-resistant pathogens including A. baumannii.
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U2 - 10.1038/s41598-021-86400-1
DO - 10.1038/s41598-021-86400-1
M3 - Article
C2 - 33782435
AN - SCOPUS:85103600652
SN - 2045-2322
VL - 11
SP - 1
EP - 16
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 7050
ER -