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Microorganisms make a wealth of unusual metabolites that have a secondary role in the organism’s ontogeny, such as self-defense, aggression, or even communication as the need arises. These compounds often have biological activity valuable to humankind (1). Nevertheless, as valuable as antibiotics and other naturally occurring drugs have been over the past 60 years, their future use is threatened by now widespread resistance to antibiotics among human, animal, and agricultural pathogens. Despite the fact that microbial metabolites are being found continually by pharmaceutical companies through targeted screening programs, fewer and fewer fundamentally new types of drugs have been found in this way during the past two decades (2). Combinatorial biosynthesis seeks to help remedy this situation through genetic engineering, the goal of which is to make new antibiotics by exploiting the microbial genes and enzymes that make these substances, thereby aiming to discover drugs that cannot be found in nature. Combinatorial biosynthesis has been especially successful with bacterial polyketide synthases (PKSs), enzymes that, in essence, polymerize simple fatty acids into a myriad of chemical structures called “polyketides” (3). The polyketides discovered so far number into the thousands and are usually categorized on the basis of their structures: one type resembles branched-chain fatty acids formed into large carbocyclic rings (macrolides), and another type contains two or more aromatic rings fused into polycyclic structures, although nature has invented many variations of these and other structural themes (3). Modular type I PKSs consisting of one or more large multifunctional proteins make the first type, and iterative type II PKSs, complexes of several largely monofunctional proteins, make the second type (4, 5). After the first bacterial PKS genes were cloned between 1989 and 1991, extensive structure–function investigations of both types of PKSs were carried out, and more recently, this has led to …

Microbial polyketide synthases: More and more prolific