Discovery of dap-3 polymyxin analogues for the treatment of multidrug-resistant gram-negative nosocomial infections

Magee T.V.; Brown M.F.; Starr J.T.; Ackley D.C.; Abramite J.A.; Aubrecht J.; Butler A.; Crandon J.L.; Dib-Hajj F.; Flanagan M.E.; Granskog K.; Hardink J.R.; Huband M.D.; Irvine R.; Kuhn M.; Leach K.L.; Li B.; Lin J.; Luke D.R.; Macvane S.H.; Miller A.A.; McCurdy S.; McKim J.M.; Nicolau D.P.; Nguyen T.-T.

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Discovery of dap-3 polymyxin analogues for the treatment of multidrug-resistant gram-negative nosocomial infections

机译：发现dap-3多粘菌素类似物用于治疗多重耐药的革兰氏阴性医院感染

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We report novel polymyxin analogues with improved antibacterial in vitro potency against polymyxin resistant recent clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa. In addition, a human renal cell in vitro assay (hRPTEC) was used to inform structure-toxicity relationships and further differentiate analogues. Replacement of the Dab-3 residue with a Dap-3 in combination with a relatively polar 6-oxo-1-phenyl-1,6-dihydropyridine-3- carbonyl side chain as a fatty acyl replacement yielded analogue 5x, which demonstrated an improved in vitro antimicrobial and renal cytotoxicity profiles relative to polymyxin B (PMB). However, in vivo PK/PD comparison of 5x and PMB in a murine neutropenic thigh model against P. aeruginosa strains with matched MICs showed that 5x was inferior to PMB in vivo, suggesting a lack of improved therapeutic index in spite of apparent in vitro advantages.

机译：我们报告新型多粘菌素类似物对鲍曼不动杆菌和铜绿假单胞菌对多粘菌素抗药性的最新临床分离株具有增强的体外抗菌作用。此外，人类肾细胞体外测定法（hRPTEC）用于告知结构-毒性关系并进一步区分类似物。用Dap-3取代Dab-3残基并结合相对极性的6-氧-1-苯基-1,6-二氢吡啶-3-羰基侧链作为脂肪酰基取代基，产生类似物5x相对于多粘菌素B（PMB）的体外抗菌和肾脏细胞毒性谱。然而，在鼠中性粒细胞减少性大腿模型中，铜绿假单胞菌菌株与匹配的MIC相比，体内5x和PMB的PK / PD比较显示5x在体内劣于PMB，尽管在体外具有明显优势，但缺乏改善的治疗指数。

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《Journal of Medicinal Chemistry》 |2013年第12期|共15页
作者
Magee T.V.; Brown M.F.; Starr J.T.; Ackley D.C.; Abramite J.A.; Aubrecht J.; Butler A.; Crandon J.L.; Dib-Hajj F.; Flanagan M.E.; Granskog K.; Hardink J.R.; Huband M.D.; Irvine R.; Kuhn M.; Leach K.L.; Li B.; Lin J.; Luke D.R.; Macvane S.H.; Miller A.A.; McCurdy S.; McKim J.M.; Nicolau D.P.; Nguyen T.-T.;
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正文语种 eng
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Discovery; polymyxin; infections;

机译：发现;多粘菌素;感染;

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1. Discovery of dap-3 polymyxin analogues for the treatment of multidrug-resistant gram-negative nosocomial infections [J] . Magee T.V., Brown M.F., Starr J.T., Journal of Medicinal Chemistry . 2013,第12期

机译：发现dap-3多粘菌素类似物用于治疗多重耐药的革兰氏阴性医院感染
2. Combination therapy with polymyxin B for the treatment of multidrug-resistant Gram-negative respiratory tract infections. [J] . Sobieszczyk ME, Furuya EY, Hay CM, The Journal of Antimicrobial Chemotherapy . 2004,第2期

机译：与多粘菌素B联合治疗多药耐药的革兰氏阴性呼吸道感染。
3. Parenteral polymyxin B use in patients with multidrug-resistant gram-negative bacteremia and urinary tract infections: a retrospective case series. [J] . Pastewski AA, Caruso P, Parris AR, The annals of pharmacotherapy . 2008,第9期

机译：肠外多粘菌素B在具有多重耐药性的革兰氏阴性菌血症和尿路感染患者中的使用：回顾性病例系列。
4. Efficacy and Safety of Polymyxin B in the Treatment of Infections Caused by Multidrug- Resistant Gram-Negative Infections: A Retrospective Review [C] . Oh HML, Gan LH, Wee I International Congress of Chemotherapy and Infection . 2009

机译：多种抗革兰阴性感染治疗感染治疗感染的疗效和安全性：回顾性综述
5. Isolation and Characterization of Lactobacillus parafarraginis KU495926 Inhibiting Multidrug-Resistant and Extended Spectrum Beta-Lactamase Gram-Negative Bacteria [D] . Allen-McFarlane, Rachelle S. 2018

机译：副乳杆菌KU495926抑制多药耐药和广谱β-内酰胺酶革兰氏阴性菌的分离和鉴定
6. Polymyxin B Nephrotoxicity and Efficacy against Nosocomial Infections Caused by Multiresistant Gram-Negative Bacteria [O] . John P. Ouderkirk, Jill A. Nord, Glenn S. Turett, 2003

机译：多粘菌素B对多重耐药革兰氏阴性菌引起的医院感染的肾毒性和功效
7. Polymyxin B Nephrotoxicity and Efficacy against Nosocomial Infections Caused by Multiresistant Gram-Negative Bacteria [O] . Ouderkirk, John P., Nord, Jill A., Turett, Glenn S., 2003

机译：多粘菌素B对多重耐药革兰氏阴性菌引起的医院感染的肾毒性和功效
8. Multidrug-Resistant Gram-Negative Bacterial and Carbapenem-Resistant Enterobacteriaceae Infections in the Department of the Navy: Annual Report 2013. [R] . Meddaugh, P., Chukwuma, U. 2015

机译：海军部多重抗药性革兰氏阴性细菌和耐碳青霉烯类肠杆菌感染：2013年年度报告。

Discovery of dap-3 polymyxin analogues for the treatment of multidrug-resistant gram-negative nosocomial infections

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