Reinforcing Lipid A Acylation on the Cell Surface of Acinetobacter baumannii Promotes Cationic Antimicrobial Peptide Resistance and Desiccation Survival
Authors: Boll Joseph M. , Tucker Ashley T. , Klein Dustin R. , Beltran Alexander M. , Brodbelt Jennifer S. , Davies Bryan W. , Trent M. Stephen 
Published: May 2015

Acinetobacter baumannii
is an emerging Gram-negative pathogen found in hospitals and intensive care units. In order to persist in hospital environments,
A. baumannii
withstands desiccative conditions and can rapidly develop multidrug resistance to conventional antibiotics. Cationic antimicrobial peptides (CAMPs) have served as therapeutic alternatives because they target the conserved lipid A component of the Gram-negative outer membrane to lyse the bacterial cell. However, many Gram-negative pathogenic bacteria, including
A. baumannii
, fortify their outer membrane with hepta-acylated lipid A to protect the cell from CAMP-dependent cell lysis. Whereas in
Escherichia coli
and
Salmonella
, increased production of the outer membrane acyltransferase PagP results in formation of protective hepta-acylated lipid A, which reinforces the lipopolysaccharide portion of the outer membrane barrier,
A. baumannii
does not carry a gene that encodes a PagP homolog. Instead,
A. baumannii
has evolved a PagP-independent mechanism to synthesize protective hepta-acylated lipid A. Taking advantage of a recently adapted
A. baumannii
genetic recombineering system, we characterized two putative acyltransferases in
A. baumannii
designated LpxL
Ab
(
A. baumannii
LpxL) and LpxM
Ab
(
A. baumannii
LpxM), which transfer one and two lauroyl (C
12:0
) acyl chains, respectively, during lipid A biosynthesis. Hepta-acylation of
A. baumannii
lipid A promoted resistance to vertebrate and polymyxin CAMPs, which are prescribed as last-resort treatment options. Intriguingly, our analysis also showed that LpxM
Ab
-dependent acylation of lipid A is essential for
A. baumannii
desiccation survival, a key resistance mechanism for survival in hospital environments. Compounds that inhibit LpxM
Ab
-dependent hepta-acylation of lipid A could act synergistically with CAMPs to provide innovative transmission prevention strategies and treat multidrug-resistant infections.

IMPORTANCE
Acinetobacter baumannii
infections can be life threatening, and disease can progress in a variety of host tissues. Current antibiotic regimen and disinfectant strategies have failed to limit nosocomial
A. baumannii
infections. Instead, the rate of
A. baumannii
infection among health care communities has skyrocketed due to the bacterium's adaptability. Its aptitude for survival over extended periods on inanimate objects, such as catheters, respirators, and surfaces in intensive care units, or on the hands of health care workers and its ability to rapidly develop antibiotic resistance make
A. baumannii
a threat to health care communities. Emergence of multidrug- and extremely drug-resistant
A. baumannii
illustrates the ineffectiveness of current prevention and treatment options. Our analysis to understand how
A. baumannii
resists cationic antimicrobial peptide (CAMP)-mediated and desiccative killing revealed two lipid A acyltransferases that produce protective hepta-acylated lipid A. Our work suggests that inhibiting lipid A biosynthesis by targeting the acyltransferase LpxM
Ab
(
A. baumannii
LpxM) could provide a novel target to combat this pathogen.