The exploitation of microorganisms has advanced significantly during the past few years with technological advances in enzyme isolation and molecular biology which have contributed to a vast accumulation of microbial information. These biotechnological manipulations of microbes have allowed scientists to create useful biosynthetic products that are almost impossible to mimic by totally synthetic techniques. Many times in the development of naturally-occurring antibiotics, there is a need to modify the chemical structure in order to improve the clinical utility, minimize undesirable side effects and in general examine the relationship of the antibiotic's structure and the biological activity of its corresponding pharmacophore. We believe that through the exploitation of microbial biosynthetic enzymatic systems, we will be able t o produce a variety of structurally novel antibiotics with varying degrees of antimicrobial specificity. We are proposing that it is likely a set of intermingled biosynthetic enzymatic and/or regulatory traits associated with various macrolide antibiotics will be capable of creating a wide variety of novel medicinal agents which may be useful in the treatment of opportunistic infections. Parent organisms which produce clinically useful macrolide antibiotics, several of which are useful in the treatment of AIDS-related opportunistic infections, will be used for producing new hybrid antibiotics. The varying degrees of antibiotic specificity of the macrolide antibiotics, even within the same numbered lactone ring systems, is well documented. We are proposing experiments designed to intermingle these various structural aspects of this group of antibiotics to produce novel antibiotics in an effort to further broaden the spectrum of antibiotic activities.
