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Investigation of antibacterial mode of action for traditional and amphiphilic aminoglycosides.

Udumula V, Ham YW, Fosso MY, Chan KY, Rai R, Zhang J, Li J, Chang CW.

Bioorg Med Chem Lett. 2013 Mar 15;23(6):1671-5.

Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA.




Aminoglycoside represents a class of versatile and broad spectrum antibacterial agents. In an effort to revive the antibacterial activity against aminoglycoside resistant bacteria, our laboratory has developed two new classes of aminoglycoside, pyranmycin and amphiphilic neomycin (NEOF004). The former resembles the traditional aminoglycoside, neomycin. The latter, albeit derived from neomycin, appears to exert antibacterialaction via a different mode of action. In order to discern that these aminoglycoside derivatives have distinct antibacterial mode of action, RNA-binding affinity and fluorogenic dye were employed. These studies, together with our previous investigation, confirm that pyranmycin exhibit the traditionalantibacterial mode of action of aminoglycosides by binding toward the bacterial rRNA. On the other hand, the amphiphilic neomycin, NEOF004 disrupts the bacterial cell wall. In a broader perspective, it verifies that structurally modified neomycin can exert different antibacterial mode of actionleading to the revival of activity against aminoglycoside resistant bacteria.

Copyright © 2013 Elsevier Ltd. All rights reserved.


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A new approach for fighting against infectious diseases has been reported recently (Chang et al., Bioorg. Med. Chem. Lett. 2013, 23, 1671). Chang’s group has synthesized an amphiphilic aminoglycoside, NEOF004 from neomycin, a naturally occurring aminoglycoside antibiotic. The main structural difference of NEOF004 is the attachment of a linear hexadecanoyl group at the 5″ position of ring III of neomycin. Traditional aminoglycoside antibiotics exert their antibacterial activity by first entering the bacteria (both Gram positive and Gram negative) through a ATP-driven uptake process. The aminoglycosides inside the bacteria then bind selectively toward the A-site decoding region of the 16S rRNA and interfere the protein biosynthesis, which leads to cell death. Anaerobic or facultative bacteria are intrinsically resistant against traditional aminoglycosides due to the lack of ATP-driven uptake mechanisms. However, NEOF004 was noted for its broad spectrum activity against a panel of aminoglycoside resistant bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). The antibacterial activity of NEOF004 against VRE is of particular interest since VRE is a facultative bacterium  that has developed high levels of resistance against traditional aminoglycosides, including neomycin, kanamycin, amikacin and gentamicin. This surprising activity implies that NEOF004 has a different antibacterial mode of action from the traditional aminoglycosides. By using a fluorogenic SYTOX dye, Chang’s laboratory confirms that NEOF004 can cause damage to the bacterial membrane, which explains the activity of NEOF004 against VRE. This result also supports the observed synergism between NEOF004 and traditional aminoglycosides reported from Chang’s group. Drug development often takes more than ten years and billions of dollars of investment. Nevertheless, rapidly evolving and emerging drug resistance has made many of the clinically used antibiotics obsolete. This article shows an example that simple chemical modifications on an old drug, which can be achieved in a short time, can alter the antimicrobial mode of action and yield new biological activities or applications. Many obsolete old drugs may be ineffective but their scale-up production processes have been well-established. Using the concept reported herein and taking the advantage of the ample quantity of these old drugs, a potentially useful method for facile new drug development has been illustrated.


Investigation of antibacterial mode of action for traditional and amphiphilic aminoglycosides