Three new 22-membered macrolactone antibiotics, atacamycins A-C, were produced by Streptomyces sp. C38, a strain isolated from a hyper-arid soil collected from the Atacama Desert in the north of Chile. The metabolites were discovered in our HPLC-diode array screening and isolated from the mycelium by extraction and chromatographic purification steps. The structures were determined by mass spectrometry and NMR experiments. Atacamycins A, B and C exhibited moderate inhibitory activities against the enzyme phosphodiesterase (PDE-4B2), whereas atacamycin A showed a moderate antiproliferative activity against adeno carcinoma and breast carcinoma cells.