acnes, a causative agent in the skin disease acne vulgaris, are naturally resistant to mupirocin. Most strains of Pseudomonas fluorescens are also resistant to mupirocin as they produce the antibiotic and it’s possible other species of Pseudomonas may be resistant as well. The mechanism of action of mupirocin differs from other clinical antibiotics, rendering cross-resistance to other antibiotics unlikely. However, the MupA gene may co-transfer with other antibacterial resistance genes. This has been observed already with resistance genes for triclosan, tetracycline, and trimethoprim. It may also result in overgrowth of non-susceptible organisms. Mechanism of action Pseudomonic acid inhibits isoleucine tRNA synthetase in bacteria, leading to depletion of isoleucyl-tRNA and accumulation of the corresponding uncharged tRNA. Depletion of isoleucyl-tRNA results in inhibition of protein synthesis. The uncharged form of the tRNA binds to the aminoacyl-tRNA binding site of ribosomes, triggering the formation of (p)ppGpp, which in turn inhibits RNA synthesis. The combined inhibition of protein synthesis and RNA synthesis results in bacteriostasis. This mechanism of action is shared with furanomycin, an analog of isoleucine. Biosynthesis Mupirocin is a mixture of several pseudomonic acids, with pseudomonic acid A (PA-A) constituting greater than 90% of the mixture. Also present in mupirocin are pseudomonic acid B with an additional hydroxyl group at C8, pseudomonic acid C with a double bond between C10 and C11, instead of the epoxide of PA-A, and pseudomonic acid D with a double bond at C4` and C5` in the 9-hydroxy-nonanoic acid portion of mupirocin. Biosynthesis of pseudomonic acid A The 74 kb mupirocin gene cluster contains six multi-domain enzymes and twenty-six other peptides (Table 1). Four large multi-domain type I polyketide synthase (PKS) proteins are encoded, as well as several single function enzymes with sequence similarity to type II PKSs. Therefore, it is believed that mupirocin is constructed by a mixed type I and type II PKS system. The mupirocin cluster exhibits an atypical acyltransferase (AT) organization, in that there are only two AT domains, and both are found on the same protein, MmpC. These AT domains are the only domains present on MmpC, while the other three type I PKS proteins contain no AT domains. The mupirocin pathway also contains several tandem acyl carrier protein doublets or triplets. This may be an adaptation to increase the throughput rate or to bind multiple substrates simultaneously. Pseudomonic acid A is the product of an esterification between the 17C polyketide monic