1. Exploring bacterial metalloproteases as promising drug targets
- Author
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Alhayek, Alaa
- Abstract
Microbial infection and the rise of antibiotic resistance pose a serious threat to public health. To tackle bacterial infection and resistance, new bacterial targets and non-antibiotic treatment options need to be identified. Virulence factors are gaining attention these days as they play crucial roles in bacterial pathogenicity. As their inhibition does not kill the bacteria, the selection pressure for emerging new resistant mutants is reduced, while also assisting the host immune system in eliminating the disarmed bacteria. Extracellular bacterial collagenases are the etiologic features of many bacterial infections. They are metalloproteases characterized by their ability to digest the main scaffolds of the extracellular matrix, exposing deep tissue to bacteria and other toxins. As the inhibition of virulence factors is considered one powerful non-antibiotic strategy, full characterization of these targets is essential to understand their role during infection. Furthermore, pre-clinical models imitating the infection need to be developed to decipher the role of virulence targets and their inhibitors in pathophysiological settings. This study addresses the characterization and validation of three bacterial collagenases and their inhibitors: collagenase Q1 (ColQ1) of Bacillus cereus, Collagenase H (ColH) of Clostridium histolyticum, and elastase B (LasB) of Pseudomonas aeruginosa. To promote our understanding of the pathological contribution of bacterial collagenases and to characterize the activity of small-molecule collagenase inhibitors as therapeutic agents, we developed pre-clinical systems modeling the infection settings and validating the collagenases and their inhibitors. These systems include in vitro cell-based, ex vivo pig skin, and in vivo Galleria mellonella larvae models. Furthermore, advanced microscopic techniques as well as in vitro biological and bioanalytical assays were used to evaluate the effects shown in these models. The newly discovered inhibitors investigated in this study are characterized with their potency, selectivity, and chemical stability, which many previously reported inhibitors lack. The findings of this work shed light on the roles of bacterial collagenases during bacterial infection – in particular in disease progression – and the effect of their inhibition with small-molecule antivirulence agents, which could represent an effective therapeutic strategy.
- Published
- 2022