Efficacy of the small molecule inhibitor of Lipid II BAS00127538 against Acinetobacter baumannii

Drug Design, Development and Therapy Dovepress open access to scientific and medical research R a p i d C o m m u n i c at i o n Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 5.196.129.157 on 12-Jul-2018 For personal use only. Open Access Full Text Article Efficacy of the small molecule inhibitor of Lipid II BAS00127538 against Acinetobacter baumannii This article was published in the following Dove Press journal: Drug Design, Development and Therapy 8 August 2014 Number of times this article has been viewed Erik PH de Leeuw Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA Introduction Correspondence: Erik PH de Leeuw Institute of Human Virology of the University of Maryland Baltimore School of Medicine, 725 West Lombard Street, Baltimore, MD 21201, USA Tel +1 410 706 1970 Fax +1 410 706 7583 Email Lipid II is an essential precursor in cell wall biosynthesis, and is a validated antibacterial drug target. It is comprised of a hydrophilic head group that includes a peptidoglycan subunit composed of N-acetylglucosamine and N-acetylmuramic acid. The cell wall of all bacteria comprises this polymer of alternating amino sugars. The peptidoglycan layer of Gram-negative bacteria is generally much smaller than the Gram-positive cell wall (1.5 versus ∼20 layers).1 The natural glycopeptide antibiotic vancomycin was the first compound discovered to kill bacteria by targeting Lipid II. Currently, vancomycin serves as a principal treatment for infections caused by all major Gram-positive pathogens, including methicillinresistant Staphylococcus aureus. However, resistance to vancomycin is increasing and a number of vancomycin insensitive strains have been described. Two resistance mechanisms have been described in these strains: affinity trapping of vancomycin by increased production of cell wall monomers, and change in metabolism and structure of teichoic acid.2 Reported resistance in clinical isolates resulted from replacing the carboxy terminal D-alanyl-D-alanine target for vancomycin by D-alanyl-D-lactate.3 Resistance to vancomycin appeared over 20 years, predominantly because vancomycin was reserved as a last resort antibiotic to prolong development of resistance. The vancomycin derivative telavancin (Vibativ®; Theravance Biopharma US, Inc., South San Francisco, CA, USA) was approved by the Food and Drug Administration for complicated skin and skin structure infections in 2009 and more recently for hospitalacquired pneumonia when alternative treatments are not suitable. Two next-generation 1061 submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2014:8 1061–1064 Dovepress © 2014 de Leeuw. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php http://dx.doi.org/10.2147/DDDT.S68020 Powered by TCPDF (www.tcpdf.org) Objective: To test the activity of a small molecule compound that targets Lipid II against Acinetobacter baumannii. Methods: Susceptibility to small molecule Lipid II inhibitor BAS00127538 was assessed using carbapenem- and colistin-resistant clinical isolates of A. baumannii. In addition, synergy between colisitin and this compound was assessed. Results: Small molecule Lipid II inhibitor BAS00127538 potently acts against A. baumannii and acts synergistically with colistin. Conclusion: For the first time, a compound that targets Lipid II is described that acts against multi-drug resistant isolates of A. baumannii. The synergy with colistin warrants further lead development of BAS00127538. Keywords: Lipid II, Acinetobacter baumannii, drug development Dovepress Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 5.196.129.157 on 12-Jul-2018 For personal use only. de Leeuw vancomycin-derived glycopeptides that bind Lipid II are currently in clinical trials: dalbavancin hydrochloride (Durata Therapeutics, Inc., Chicago, IL, USA) and oritavancin (The Medicines Company, Parsippany-Troy Hills, NJ, USA). Resistance against commonly used classical antibiotics has emerged in all major classes of both Gram-positive and Gram-negative pathogens, including S. aureus, E nterococcus faecium, Pseudomonas aeruginosa, and Acinetobacter baumannii. 4,5 Multi-drug resistant A. baumannii is an increasingly important Gram-negative pathogen, particularly in hospital settings.4 The types of infections caused by this pathogen include pneumonia, endocarditis, bacteremia, skin and soft tissue infections, and meningitis.4,6–8 Factors that contribute to pathogenesis of this organism include iron acquisition, membrane polysaccharides and vesicles, biofilm formation, and penicillin-binding proteins.9 We have recently described small molecule inhibitors of Lipid II for the first time.10 Our most promising compound, BAS00127538, was highly active against Gram-positive species and showed activity against Gram-negative species also, albeit reduced. This compound binds to Lipid II differently than other compounds, affects cell wall biosynthesis, and showed efficacy in vivo.10 Since vancomycin, dalbavancin, and oritavancin fail to demonstrate any notable activity against A. baumannii, we tested activity of our lead small molecule Lipid II inhibitor BAS00127538 (Figure 1) against this species. Materials and methods Strains Twelve isolates of carbapenem- and/or colistin-sensitive or resistant A. baumannii were obtained from the Laboratory of Pathology, University of Maryland Baltimore School of Medicine (Baltimore, MD, USA). All isolates were c haracterized by Etest (meropenem) or minimum inhibitory concentration (MIC) (colistin) according to the Clinical and Laboratory Standards Institute guidelines as indicated in Table 1. A. baumannii ATCC 19606 was included as a reference strain for quality control testing. Antimicrobial agents Colistin and meropenem were obtained from LKT Laboratories, Inc., (St Paul, MN, USA). Vancomycin was purchased from Sigma-Aldrich Co (St Louis, MO, USA). BAS00127538 was obtained from Asinex (Winston-Salem, NC, USA). Synergy screen Synergy was determined by checkerboard method.11 The stock solutions and serial two-fold dilutions of each drug to at least double the MIC were prepared according to the recommendations of the National Committee for Clinical Laboratory Standards immediately prior to testing. A total of 50 µL of Mueller–Hinton broth was distributed into each well of the microdilution plates. T (...truncated)