Reinforcing Lipid A Acylation on the Cell Surface of Acinetobacter baumannii Promotes Cationic Antimicrobial Peptide Resistance and Desiccation Survival.
Reinforcing Lipid A Acylation on the Cell Surface of Acinetobacter baumannii Promotes Cationic Antimicrobial Peptide Resistance and Desiccation Survival.
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DOI：
10.1128/mbio.00478-15
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发表时间：
2015-05-19
期刊：
影响因子：
6.4
通讯作者：
Trent MS
中科院分区：
文献类型：
--
作者：
Boll JM;Tucker AT;Klein DR;Beltran AM;Brodbelt JS;Davies BW;Trent MS
鲍曼不动杆菌是一种新出现的革兰氏阴性病原体，发现于医院和重症监护病房。为了能在医院环境中存活，鲍曼不动杆菌能耐受干燥的条件，并能迅速对常规抗生素产生多药耐药性。阳离子抗菌肽（CAMPs）已成为治疗替代品，因为它们靶向革兰氏阴性外膜的保守脂质A成分来溶解细菌细胞。然而，许多革兰氏阴性病原菌，包括鲍曼不动杆菌，用七酰化脂质A强化其外膜，以保护细胞免受cAMP依赖性细胞裂解。而在大肠杆菌和沙门氏菌中，外膜酰基转移酶PagP的产生增加导致形成保护性七酰化脂质A，其增强外膜屏障的脂多糖部分，鲍曼不动杆菌不携带编码PagP同源物的基因。相反，鲍曼不动杆菌已经进化出一种PagP非依赖性机制来合成保护性七酰化脂质A。利用最近适应的鲍曼不动杆菌基因重组工程系统，我们表征了鲍曼不动杆菌中两种推定的酰基转移酶，命名为LpxLAb（鲍曼不动杆菌LpxL）和LpxMAb（鲍曼不动杆菌LpxM），其在脂质A生物合成期间分别转移一个和两个月桂酰基（C12：0）酰基链。鲍曼不动杆菌脂质A的七酰化促进了对脊椎动物和多粘菌素CAMP的耐药性，这是处方的最后治疗选择。有趣的是，我们的分析还表明，脂A的LpxMAb依赖性酰化是鲍曼不动杆菌脱水存活所必需的，这是在医院环境中存活的关键耐药机制。抑制脂质A的LpxMAb依赖性七酰化的化合物可以与CAMP协同作用，以提供创新的传播预防策略并治疗多药耐药感染。鲍曼不动杆菌感染可危及生命，并且疾病可在多种宿主组织中进展。目前的抗生素治疗方案和消毒剂策略未能限制医院内鲍曼不动杆菌感染。相反，由于这种细菌的适应性，医疗保健社区的鲍曼不动杆菌感染率飙升。它在无生命物体上长时间生存的能力，如导管，呼吸机和重症监护病房的表面，或在卫生保健工作者的手上，以及它迅速发展抗生素耐药性的能力，使鲍曼不动杆菌成为卫生保健社区的威胁。多重耐药和极端耐药鲍曼不动杆菌的出现说明了目前预防和治疗方案的无效性。我们的分析，以了解鲍曼不动杆菌如何抵抗阳离子抗菌肽（CAMP）介导的和干燥的杀伤揭示了两个脂质A酰基转移酶，产生保护性七酰化脂质A。我们的工作表明，通过靶向酰基转移酶LpxMAb（鲍曼不动杆菌LpxM）来抑制脂质A的生物合成可以提供一个新的靶标来对抗这种病原体。
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 LpxLAb (A. baumannii LpxL) and LpxMAb (A. baumannii LpxM), which transfer one and two lauroyl (C12:0) 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 LpxMAb-dependent acylation of lipid A is essential for A. baumannii desiccation survival, a key resistance mechanism for survival in hospital environments. Compounds that inhibit LpxMAb-dependent hepta-acylation of lipid A could act synergistically with CAMPs to provide innovative transmission prevention strategies and treat multidrug-resistant infections. 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 LpxMAb (A. baumannii LpxM) could provide a novel target to combat this pathogen.