One reason why the bacteria that cause chronic infections may not be killed or inhibited effectively by antibiotics is that these bacteria infect as biofilms, or matrix-encased aggregates of bacteria growing adherent to each other and/or a surface that are relatively resistant to killing by many means.
We showed previously that exposure to tobramycin, the antibiotic used most frequently to treat people with CF and other chronic lung infections, induces some bacteria to form more biofilm. This response, which occurs in the key CF pathogenic bacterium Pseudomonas aeruginosa, leads to even more resistance to subsequent killing. That is, the many bacteria that survive most treatments with tobramycin would grow as resistant biofilm. Therefore, this response to tobramycin may lead to insufficient clinical response to this important antibiotic.
We have also found that tobramycin-mediated biofilm formation requires a signaling pathway specific to bacteria, the cyclic diguanylate (cdg) pathway, in laboratory strains of P. aeruginosa.
These observations have led to four current lines of investigation in the Hoffman laboratory, based upon the following questions:
- How common does this response occur in clinical isolates of P. aeruginosa from CF patients (i.e., what is the clinical relevance of this effect)?
- Can we use small molecules to inhibit cdg signaling to inhibit biofilm induction, and improve killing by tobramycin and other antibiotics?
- What is the entire bacterial signaling pathway in response to tobramycin, and other antibiotics, that leads to biofilm induction, and can we inhibit additional steps?
- What other features of the CF airway might favor biofilm formation by pathogenic bacteria?
Hoffman LR; D'Argenio DA; MacCoss MJ; Zhang Z; Jones RA; Miller SI; Aminoglycoside Antibiotics Induce Bacterial Biofilm Formation. Nature, 2005. 436(7054):1171-5.
Hoffman, LR; D’Argenio, DA; Bader, MW; Miller, SI. Microbial recognition of antibiotics: Ecological, physiological, and therapeutic implications. Microbe. 2007. 2(4):175-182.
Miller, SI; Hoffman, LR, Sanowar, S. Did bacterial sensing of host environments evolve from sensing within microbial communities? Cell Host Microbe. 2007. 1(2):85-7.