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Abstract: The rapid emergence of multiply drug resistant (MDR) bacterial pathogens poses a major threat for human health. In recent years, genome sequencing unveiled many poorly expressed antibiotic clusters in actinomycetes. Here we report a well-defined ecological collection of over 800 actinomycetes obtained from sites in the Himalaya and Qinling mountains, and use these in a concept study to see how efficiently antibiotics can be elicited against MDR pathogens isolated recently from the clinic. Using 40 different growth conditions, 96 actinomycetes were identified – predominantly Streptomyces – that produced antibiotics with efficacy against the MDR clinical isolates referred to as ESKAPE pathogens: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginos and/or Enterobacter cloacae. Antimicrobial activities that fluctuated strongly with growth conditions were correlated to specific antibiotics, including borrelidin, resistomycin, carbomethoxy-phenazine and 6,7,8- and 5,6,8-trimethoxy-3-methylisocoumarin, of which the latter was not previously described. Our work provides insight into the potential of actinomycetes as producers of drugs with efficacy against recently emerged clinical isolates and also underlines the importance of targeting a specific pathogen.