Novel Combination Therapy for Staphylococcus aureus Pneumonia

描述(申请人提供)：近年来，由金黄色葡萄球菌引起的疾病的发病率/严重程度令人震惊地增加，特别是由社区相关的和医院获得的甲氧西林耐药菌株引起的疾病，需要新的有效的抗菌策略。令人不安的发现是，这些菌株产生更多决定毒力的毒素，包括超抗原(SAG)，这要求使用在葡萄球菌感染不同阶段作用的药物组合进行多管齐下的攻击。而抗菌药物 例如抑制细菌毒素产生利奈唑胺是有用的，似乎只有抑菌剂 效果不是很好。这归因于两个主要原因。(I)抑菌剂未能完全停止体内毒素的产生。(Ii)在临床情况下，由感染金黄色葡萄球菌至开始进行抗菌治疗，几乎总是有一段很长的时间延迟。在这一延迟期间，已经产生了大量致病性外毒素。不幸的是，抑菌剂对预先形成的外毒素没有活性。因此，抗体可以用来中和治疗开始前产生的毒素，以及灭活尽管进行了抗菌治疗而产生的残留毒素。这种抗体将与抑菌剂协同作用。由于SAG是金黄色葡萄球菌最致病的外毒素之一，体内中和SAG可能是首选的方法。此外，SAG具有强大和非特异性刺激免疫系统继而诱导无反应或无能的独特能力。SAG，从而转移对细菌的免疫反应，从而帮助细菌免疫逃避。因此，在金黄色葡萄球菌感染期间，刺激先天免疫系统也是有益的。因此，我们建议联合使用抑菌药物、利奈唑胺、超抗原中和抗体和免疫调节剂，以提高天然免疫力，从而有效地控制/消除金黄色葡萄球菌感染。这一新方法的有效性将使用健壮的人类白细胞抗原II类转基因小鼠模型进行测试。一种高致病性金黄色葡萄球菌菌株将在人类白细胞抗原-DR3转基因小鼠身上诱导致命性肺炎，该菌株会产生大量的SAG，葡萄球菌肠毒素B(SEB)。为了模拟临床情况，在感染开始后，治疗将以2小时为增量延迟。小鼠将不接受治疗或接受利奈唑胺、人-鼠嵌合中和抗SEB抗体或同型对照抗体和Toll样受体(TLR)-2激动剂Pam2CSK4的各种组合治疗。将研究防止死亡的保护措施。因此，我们将建立一种针对致死性金黄色葡萄球菌感染的有效联合疗法，并确定联合疗法的治疗窗口。

DESCRIPTION (provided by applicant): The alarming increase in the incidence/severity of diseases caused by Staphylococcus aureus in recent years, particularly those caused by community-associated and hospital-acquired methicillin resistant strains, call for novel effective antibacterial strategies. The disturbing findings that such strains produce more virulence-determining toxins, including superantigens (SAg), mandate a multipronged attack using a combination of drugs that act at different stages of staphylococcal infection. While antibacterials such as linezolid, which inhibit bacterial toxin production, are useful, bacteriostatics alone seem to be not very effective. This is attributed to two major reasons. (i) Bacteriostatics fail to completely shut down toxin production in vivo. (ii) In the clinical settings, there is almost alway a significant time delay between the onset of S. aureus infection and initiation of antibacterial therapy. During this delay, significant quantities of pathogenic exotoxins have already been produced. Unfortunately, bacteriostatics have no activity on pre-formed exotoxins. Therefore, antibodies could be administered to neutralize toxins that were produced prior to initiation of therapy as well as to inactivate the residual toxins produced in spite of antibacterial therapy. Such antibodies would act synergistically with bacteriostatics. Since SAg are one of the most pathogenic exotoxins of S. aureus, in vivo neutralization of SAg may be the preferred approach. In addition, SAg have the unique ability to robustly and non-specifically stimulate the immune system followed by induction of unresponsiveness or anergy. SAg, thus divert the immune response against the bacterium, thereby helping in bacterial immune evasion. Therefore, stimulating the innate immune system will also be beneficial during S. aureus infections. Hence, we propose a combination therapy with the bacteriostatic drug, linezolid, neutralizing antibodies to superantigens, and immunomodulatory agents that boost innate immunity to effectively control/eliminate S. aureus infections. The effectiveness of this novel approach will be tested using the robust HLA class II transgenic mouse model. Lethal pneumonia will be induced in HLA-DR3 transgenic mice with a highly pathogenic strain of S. aureus that produces large amounts of the SAg, staphylococcal enterotoxin B (SEB). To mimic the clinical scenario, treatment will be delayed in 2-hour increments after initiation of infection. Mice will be left untreated or treated with various combinations of linezolid, human-mouse chimeric neutralizing anti-SEB antibodies or isotype control antibodies and the toll-like receptor (TLR)-2 agonist, Pam2CSK4. Protection from mortality will be studied. Thus, we would have established an effective combination therapy against lethal S. aureus infection and identified the therapeutic window of the combination therapy.