As illustrated by Fleming's famous observation that a contaminating mold inhibited bacterial growth, most antibiotics derive from substances produced by microorganisms, which may allow them to compete with other microorganisms. Noting that Streptomyces tenebrarius (which produces the aminoglycoside antibiotic tobramycin) and Pseudomonas aeruginosa (a human pathogen that can cause chronic, life-threatening infections) are both found in soil, Hoffman et al. investigated the hypothesis that P. aeruginosa had evolved adaptive responses to tobramycin. Low concentrations of tobramycin, which failed to inhibit the growth rate or alter global protein synthesis, induced the formation of biofilms (adherent communities of bacteria that contribute to antibiotic resistance and persistent infection) in P. aeruginosa and Escherichia coli. Three other aminoglycoside antibiotics also stimulated biofilm formation. By screening for mutants with attenuated biofilm production in response to tobramycin but normal biofilm formation in its absence, the authors identified three strains with mutations in a gene that they named arr (for aminoglycoside response regulator). arr was predicted to encode a membrane protein with two transmembrane domains and an EAL domain [found in cyclic di-guanosine monophosphate (c-di-GMP) phosphodiesterases]. Complementation with wild-type arr, but not a mutant in which a conserved glutamate in the EAL domain was replaced with alanine, restored tobramycin-induced biofilm formation. Membranes from arr-mutant bacteria were less effective at degrading c-di-GMP than were those from wild-type bacteria, and exogenous GTP (which inhibits c-di-GMP phosphodiesterases) inhibited tobamycin-stimulated biofilm formation in wild-type cells. Thus, the authors conclude that biofilm formation is a defensive response to aminoglycoside antibiotics that involves changes in bacterial c-di-GMP content.
L. R. Hoffman, D. A. D'Argenio, M. J. MacCoss, Z. Zhang, R. A. Jones, S. I. Miller, Aminoglycoside antibiotics induce bacterial biofilm formation. Nature 436, 1171-1175 (2005). [Online Journal]