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Antibiotic resistance versus small molecules, the chemical evolution
Author(s) -
Lee Ving J.,
Hecker Scott J.
Publication year - 1999
Publication title -
medicinal research reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.868
H-Index - 130
eISSN - 1098-1128
pISSN - 0198-6325
DOI - 10.1002/(sici)1098-1128(199911)19:6<521::aid-med4>3.0.co;2-9
Subject(s) - natural product , moiety , penicillin binding proteins , combinatorial chemistry , stereochemistry , substituent , chemistry , antibiotics , small molecule , total synthesis , biological activity , structure–activity relationship , antibiotic resistance , drug discovery , biochemistry , penicillin , in vitro
Two discovery approaches directed to addressing the problem of increasing bacterial resistance are described. The first is a program to build activity against methicillin‐resistant Staphylococcus aureus (MRSA) into the cephalosporin class of antibacterials, by enhancing affinity for PBP2a, the penicilln‐binding protein responsible for this resistance. Through stepwise improvement in potency, human serum binding, solubility, and betalactamase stability, a stable of new compunds with excellent potential as anti‐MRSA agents was realized. From this set was chosen MC‐02, 479 (RWJ‐54428), which is now undergoing extensive preclinical evaluation. The second approach explores the uridyl peptide family of antibiotics, inhibitors of bacterial translocase (mraY), whose members include the pacidamycins, mureidomycins, and napsamycins. Access to a diverse set of analogs by total synthesis was catalyzed by the discovery that hydrogenation of the 4′‐ exoenamidofuranosyl moiety causes no loss in biological activity. Depthful exploration of SAR required (1) establishment of the absolute stereochemistry of the central diaminobutyric acid (DABA) moiety and (2) determination of the stereochemistry of the 4′‐substituent on the deoxyfuranose unit. The former was accomplished by comparison of DABA derived from degradation of a natural product pacidamycin with a sample synthesized from L ‐ threonine. The biological activity of one member of a synthesized library of possible stereoisomers of the natural product established the absolute stereochemistry of the remaining centers. A variety of analogs of the natural product were prepared utilizing the synthetic methods developed, and their biological activities provide important insights into the specificity and spectrum of the antibiotic class. © 1999 John Wiley & Sons, Inc. Med Res Rev, 19, No. 6, 521–542, 1999