<jats:title>Summary</jats:title><jats:p>Glutarimide‐containing polyketides are known as potent antitumoral and antimetastatic agents. The associated gene clusters have only been identified in a few <jats:italic>Streptomyces</jats:italic> producers and <jats:italic>Burkholderia gladioli</jats:italic> symbiont. The new glutarimide‐family polyketides, denominated sesbanimides D, E and F along with the previously known sesbanimide A and C, were isolated from two marine alphaproteobacteria <jats:italic>Stappia indica</jats:italic> PHM037 and <jats:italic>Labrenzia aggregata</jats:italic> PHM038. Structures of the isolated compounds were elucidated based on 1D and 2D homo and heteronuclear NMR analyses and ESI‐MS spectrometry. All compounds exhibited strong antitumor activity in lung, breast and colorectal cancer cell lines. Subsequent whole genome sequencing and genome mining revealed the presence of the <jats:italic>trans</jats:italic>‐AT PKS gene cluster responsible for the sesbanimide biosynthesis, described as <jats:italic>sbn</jats:italic> cluster. Strikingly, the modular architecture of downstream mixed type PKS/NRPS, SbnQ, revealed high similarity to PedH in pederin and Lab13 in labrenzin gene clusters, although those clusters are responsible for the production of structurally completely different molecules. The unexpected presence of SbnQ homologues in unrelated polyketide gene clusters across phylogenetically distant bacteria, raises intriguing questions about the evolutionary relationship between glutarimide‐like and pederin‐like pathways, as well as the functionality of their synthetic products.