Surfactants have the potential to overcome natural resistance of MTB to antibiotics which is mediated by barriers that impede the penetration of drugs to their targets. A major component of this barrier is trehalose dimycolate (TDM) which surrounds the bacteria with a thick lipid shield. In this study dodecyl maltoside (DDM) was evaluated for this purpose. This surfactant is an excellent cellular permeabilizing agent with associated low toxicity. The administration of the surfactant as an aerosol into the lungs of the infected mice achieved a 5-10 times enhancement of the isoniazid (INH) treatment gauged by the reduction of the colony forming units. This study also established proof of principle that surfactants alone applied as an aerosol can reduce the bacteria count in lungs infected with MTB. The potential of the surfactant in the therapy of human cavitary TB was also investigated using a surgically removed lung from a patient with extreme drug resistant MTB (XDR-TB). A cavity in this lung was flushed with DDM solution ex-vivo. The procedure readily removed the bacteria, excessive amounts of TDM and necrotic tissue from the cavity. These studies demonstrate that DDM can disrupt the layers of TDM and free embedded MTB and, consequently, surfactants have promise as a proficient modality for the treatment of pulmonary MTB.