The marine environment is a rich source for unique actinomycete bacteria of significant biological and chemical diversity.1,2 Marine obligate and marine-derived actinomycetes have been shown to be the source of structurally diverse secondary metabolites, many of which have been shown to possess interesting anticancer properties.3 The discovery of antibiotics from this source is far less developed, but promising antibiotics such as anthracimycin provide significant motivation to explore this source further.4 Earlier, we showed that the marine-derived Streptomyces sp., strain CNB-091, produces a suite of at least five structurally unprecedented depsipeptides, salinamides A− E, that show significant antibacterial and anti-inflammatory properties.5,6 Subsequently, salinamide A was shown to possess significant inhibitory activity against RNA polymerase (RNAP) from Gram-positive and Gram-negative bacteria.7,8 As part of a collaborative program to further explore the chemical biology of the RNAP-inhibitory activity of the salinamides, we examined in more detail the extract and semi-purified fractions from the recultivation of Streptomyces sp. CNB-091 and report here the isolation of a new salinamide analog, salinamide F, which, like salinamide A, also possesses significant RNAP-inhibitory and antibacterial activity.