Division of General Internal Medicine, Los Angeles Biomedical Research Institute at Harbor-University of California at Los Angeles Medical Center, Torrance, CA, USA.
mBio. 2012 Oct 2;3(5). doi: 10.1128/mBio.00312-12. Print 2012.
New treatments are needed for extensively drug-resistant (XDR) Gram-negative bacilli (GNB), such as Acinetobacter baumannii. Toll-like receptor 4 (TLR4) was previously reported to enhance bacterial clearance of GNB, including A. baumannii. However, here we have shown that 100% of wild-type mice versus 0% of TLR4-deficient mice died of septic shock due to A. baumannii infection, despite having similar tissue bacterial burdens. The strain lipopolysaccharide (LPS) content and TLR4 activation by extracted LPS did not correlate with in vivo virulence, nor did colistin resistance due to LPS phosphoethanolamine modification. However, more-virulent strains shed more LPS during growth than less-virulent strains, resulting in enhanced TLR4 activation. Due to the role of LPS in A. baumannii virulence, an LpxC inhibitor (which affects lipid A biosynthesis) antibiotic was tested. The LpxC inhibitor did not inhibit growth of the bacterium (MIC>512 µg/ml) but suppressed A. baumannii LPS-mediated activation of TLR4. Treatment of infected mice with the LpxC inhibitor enhanced clearance of the bacteria by enhancing opsonophagocytic killing, reduced serum LPS concentrations and inflammation, and completely protected the mice from lethal infection. These results identify a previously unappreciated potential for the new class of LpxC inhibitor antibiotics to treat XDR A. baumannii infections. Furthermore, they have far-reaching implications for pathogenesis and treatment of infections caused by GNB and for the discovery of novel antibiotics not detected by standard in vitro screens.
Novel treatments are needed for infections caused by Acinetobacter baumannii, a Gram-negative bacterium that is extremely antibiotic resistant. The current study was undertaken to understand the immunopathogenesis of these infections, as a basis for defining novel treatments. The primary strain characteristic that differentiated virulent from less-virulent strains was shedding of Gram-negative lipopolysaccharide (LPS) during growth. A novel class of antibiotics, called LpxC inhibitors, block LPS synthesis, but these drugs do not demonstrate the ability to kill A. baumannii in vitro. We found that an LpxC inhibitor blocked the ability of bacteria to activate the sepsis cascade, enhanced opsonophagocytic killing of the bacteria, and protected mice from lethal infection. Thus, an entire new class of antibiotics which is already in development has heretofore-unrecognized potential to treat A. baumannii infections. Furthermore, standard antibiotic screens based on in vitro killing failed to detect this treatment potential of LpxC inhibitors for A. baumannii infections.
需要新的治疗方法来治疗广泛耐药（XDR）革兰氏阴性菌（GNB），例如鲍曼不动杆菌。先前有报道称， Toll 样受体 4（TLR4）可增强 GNB，包括鲍曼不动杆菌的细菌清除率。然而，在这里，我们发现 100％的野生型小鼠与 0％的 TLR4 缺陷型小鼠死于由鲍曼不动杆菌感染引起的败血症性休克，尽管它们具有相似的组织细菌负担。细菌脂多糖（LPS）含量和提取 LPS 激活的 TLR4 与体内毒力无关，LPS 磷酸乙醇胺修饰引起的多粘菌素耐药性也无关。但是，生长过程中更具毒性的菌株比毒性较低的菌株释放更多的 LPS，从而导致 TLR4 激活增强。由于 LPS 在鲍曼不动杆菌毒力中的作用，因此测试了一种 LpxC 抑制剂（影响脂酰基转移酶的合成）抗生素。LpxC 抑制剂未抑制细菌的生长（MIC>512μg/ml），但抑制了鲍曼不动杆菌 LPS 介导的 TLR4 激活。用 LpxC 抑制剂治疗感染的小鼠可增强调理吞噬作用杀伤，降低血清 LPS 浓度和炎症，并完全保护小鼠免受致命感染。这些结果表明，新型 LpxC 抑制剂抗生素具有治疗 XDR 鲍曼不动杆菌感染的潜在用途。此外，它们对 GNB 引起的感染的发病机理和治疗以及发现未通过标准体外筛选检测到的新型抗生素具有深远的意义。
需要新的治疗方法来治疗鲍曼不动杆菌感染，这是一种极其抗药性的革兰氏阴性菌。进行本研究是为了了解这些感染的免疫发病机理，作为确定新疗法的基础。区分毒力菌株和毒力较低菌株的主要菌株特征是在生长过程中脱落革兰氏阴性脂多糖（LPS）。一类新型抗生素，称为 LpxC 抑制剂，可阻断 LPS 的合成，但这些药物在体外均不能显示杀死鲍曼不动杆菌的能力。我们发现，LpxC 抑制剂可阻止细菌激活败血症级联反应的能力，增强了对细菌的调理吞噬作用杀伤，并保护了小鼠免受致命感染。因此，一种已经在开发中的全新抗生素类别具有前所未有的潜力，可以治疗鲍曼不动杆菌感染。此外，基于体外杀伤的标准抗生素筛选未能检测到 LpxC 抑制剂对鲍曼不动杆菌感染的这种治疗潜力。
