TY - JOUR
T1 - Surprising alteration of antibacterial activity of 5″-modified neomycin against resistant bacteria
AU - Zhang, Jianjun
AU - Chiang, Fang-I.
AU - Wu, Long
AU - Czyryca, Przemyslaw Greg
AU - Li, Ding
AU - Chang, Cheng-Wei Tom
PY - 2008/12/11
Y1 - 2008/12/11
N2 - A facile synthetic protocol for the production of neomycin B derivatives with various modifications at the 5″ position has been developed. The structural activity relationship (SAR) against aminoglycoside resistant bacteria equipped with various aminoglycoside-modifying enzymes (AMEs) was investigated. Enzymatic and molecular modeling studies reveal that the superb substrate promiscuity of AMEs allows the resistant bacteria to cope with diverse structural modifications despite the observation that several derivatives show enhanced antibacterial activity compared to the parent neomycin. Surprisingly, when testing synthetic neomycin derivatives against other human pathogens, two leads exhibit prominent activity against both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) that are known to exert a high level of resistance against clinically used aminoglycosides. These findings can be extremely useful in developing new aminoglycoside antibiotics against resistant bacteria. Our result also suggests that new biological and antimicrobial activities can be obtained by chemical modifications of old drugs. © 2008 American Chemical Society.
AB - A facile synthetic protocol for the production of neomycin B derivatives with various modifications at the 5″ position has been developed. The structural activity relationship (SAR) against aminoglycoside resistant bacteria equipped with various aminoglycoside-modifying enzymes (AMEs) was investigated. Enzymatic and molecular modeling studies reveal that the superb substrate promiscuity of AMEs allows the resistant bacteria to cope with diverse structural modifications despite the observation that several derivatives show enhanced antibacterial activity compared to the parent neomycin. Surprisingly, when testing synthetic neomycin derivatives against other human pathogens, two leads exhibit prominent activity against both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) that are known to exert a high level of resistance against clinically used aminoglycosides. These findings can be extremely useful in developing new aminoglycoside antibiotics against resistant bacteria. Our result also suggests that new biological and antimicrobial activities can be obtained by chemical modifications of old drugs. © 2008 American Chemical Society.
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U2 - 10.1021/jm800997s
DO - 10.1021/jm800997s
M3 - RGC 21 - Publication in refereed journal
C2 - 19012394
SN - 0022-2623
VL - 51
SP - 7563
EP - 7573
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 23
ER -
