Beyond antibiotics: new horizons in treating burkholderia species infections.

Antibiotic-resistant strains of pathogenic bacteria have always been an issue, but in recent times the need for new antimicro-bial treatments has never been more serious. Resistance is on the rise, while antibiotic discovery and development are on the decline [1]. The urge for new treatment modalities that go beyond antibiotics is clearly illustrated in the care of patients with chronic granulomatous disease and cystic fibrosis (CF), who are often colonized with gram-negative Burkhold-eria species that are intrinsically antibiotic resistant [2, 3]. In patients with CF, the vicious cycle of infection, sputum retention , and inflammation perpetuates itself, because host defense proteins released by neutrophils and macrophages stimulate mucus secretion and subsequent breakdown [2]. Multidrug resistance of Burk-holderia cepacia complex (Bcc), which is associated with a rapid decline in pulmonary function and increased mortality, has been found to be present in up to one-fifth of patients with CF [2, 4]. In this issue of the Journal, Greenberg and colleagues [5] provide us with exciting and promising data on the use of antisense molecules as new therapeutics for Burkholderia species infections. In this elegant study, the researchers targeted a gene called acyl carrier protein (acpP), which is known to be of importance for growth in Bcc, by making use of phosphorodiamidate morpholino oligo-mer (PMO) antisense technology. Peptide-conjugated PMOs (PPMOs) are water-soluble single-stranded DNA analogues that are resistant to degradation by ribonucle-ases and able to enter cells readily in order to bind to messenger RNA in a sequence-specific manner to prevent translation [6]. Sequence-specific approaches to inhibit bacterial replication are attractive in part because of the low likelihood of target sequence homology between pathogen and host, thus minimizing the potential for toxicity from cross-reactivity [6]. Greenberg et al [5] synthesized PPMOs directed against acpP of Bcc and tested their antimicrobial potency in vitro and in vivo. The results are exciting. Excellent efficacy of AcpP PPMO is demonstrated in vitro, in neutrophil-killing assays, and most importantly in vivo in a murine model of Bcc infection. In a mouse model of chronic granulomatous disease, AcpP PPMO–treated mice show a nearly 80% reduction in mortality, compared with water treated controls after an intraperito-neal challenge with Burkholderia multi-vorans. Importantly, mice treated with AcpP PPMO that did survive this experiment showed only limited organ damage , as demonstrated by histopathological analysis. It must be emphasized, however, that if this approach is to move forward, future critically important murine …