Abstract
Antimicrobial peptides (AMPs) are essential effectors of the host innate immune system and they represent promising molecules for the treatment of multidrug resistant microbes. A better understanding of microbial resistance to these defense peptides is thus prerequisite for the control of infectious diseases. Here, using a random mutagenesis approach, we identify the fliK gene, encoding an internal molecular ruler that controls flagella hook length, as an essential element for Bacillus thuringiensis resistance to AMPs in Drosophila. Unlike its parental strain, that is highly virulent to both wild-type and AMPs deficient mutant flies, the fliK deletion mutant is only lethal to the latter’s. In agreement with its conserved function, the fliK mutant is non-flagellated and exhibits highly compromised motility. However, comparative analysis of the fliK mutant phenotype to that of a fla mutant, in which the genes encoding flagella proteins are interrupted, indicate that B. thuringiensis FliK-dependent resistance to AMPs is independent of flagella assembly. As a whole, our results identify FliK as an essential determinant for B. thuringiensis virulence in Drosophila and provide new insights on the mechanisms underlying bacteria resistance to AMPs.
Highlights
The continuous emergence of new infectious agents, together with the worrying rise in antibiotic resistance in pathogens, constitutes a threat to human health with predictions that these will account for 20% of deaths over the coming decades (ECDC/EMEA, 2009)
Using a random mutagenesis approach, we identified the fliK gene, which encodes a protein with a flagellar hook length control motif, as an essential determinant for B. thuringiensis resistance to antimicrobial peptides (AMPs) and virulence in Drosophila
In an attempt to identify new genes involved in the resistance of B. cereus to innate immune defenses, and to AMPs, we generated, by insertion and mobilization of a mini-Tn10 transposon, a random mutagenesis library of the B. thuringiensis Bt407 strain (Lereclus et al, 1989) that we screened in a two-step strategy as described in the following
Summary
The continuous emergence of new infectious agents, together with the worrying rise in antibiotic resistance in pathogens, constitutes a threat to human health with predictions that these will account for 20% of deaths over the coming decades (ECDC/EMEA, 2009). FliK Confers Resistance to AMPs are resistant to at least one class of antibiotics and the emergence of strains resistant to several classes of antibiotics is beginning to pose serious therapeutic problems (Levy and Marshall, 2004) These data highlight the urgent need to implement new therapeutic strategies and develop new classes of antimicrobial agents to control infections. If AMPs are taken out of their natural environment and used as antimicrobial agents in a conventional clinical setting, they could exert a strong and continuous selection pressure on the bacterial population leading to rapid selection of resistant strains Such a scenario could have extremely serious consequences if it resulted in the development of cross-resistance with innate human AMPs (Bell and Gouyon, 2003; Perron et al, 2006). An accurate knowledge of the mechanisms of resistance to these compounds, and a better understanding of the environmental constraints encountered by pathogenic bacteria during the infectious process, are prerequisites to their intensive use
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