Minrovic Bradley M, Hubble Veronica B, Barker William T, Jania Leigh A, Melander Roberta J, Koller Beverly H, Melander Christian
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States.
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
ACS Med Chem Lett. 2019 Apr 17;10(5):828-833. doi: 10.1021/acsmedchemlett.9b00135. eCollection 2019 May 9.
Antibiotic resistance has significantly increased since the beginning of the 21st century. Currently, the polymyxin colistin is typically viewed as the antibiotic of last resort for the treatment of multidrug resistant Gram-negative bacterial infections. However, increased colistin usage has resulted in colistin-resistant bacterial isolates becoming more common. The recent dissemination of plasmid-borne colistin resistance genes () into the human pathogen pool is further threatening to render colistin therapy ineffective. New methods to combat antibiotic resistant pathogens are needed. Herein, the utilization of a colistin-adjuvant combination that is effective against colistin-resistant bacteria is described. At 5 μM, the lead adjuvant, which is nontoxic to the bacteria alone, increases colistin efficacy 32-fold against bacteria containing the gene and effects a 1024-fold increase in colistin efficacy against bacteria harboring chromosomally encoded colistin resistance determinants; these combinations lower the colistin minimum inhibitory concentration (MIC) to or below clinical breakpoint levels (≤2 μg/mL).
自21世纪初以来，抗生素耐药性显著增加。目前，多粘菌素通常被视为治疗多重耐药革兰氏阴性菌感染的最后一道防线。然而，多粘菌素使用的增加导致耐多粘菌素的细菌分离株变得更加常见。最近，质粒介导的多粘菌素耐药基因传播到人类病原体库中，进一步威胁到多粘菌素治疗的有效性。因此，需要新的方法来对抗抗生素耐药病原体。本文描述了一种对耐多粘菌素细菌有效的多粘菌素辅助组合的应用。在5μM时，主要辅助剂单独对细菌无毒，可使多粘菌素对携带mcr基因的细菌的效力提高32倍，并使多粘菌素对携带染色体编码的多粘菌素耐药决定簇的细菌的效力提高1024倍；这些组合将多粘菌素的最低抑菌浓度（MIC）降低到临床断点水平或以下（≤2μg/mL）。
