Inhibition of bacterial quorum sensing by biopolymer-based nanoparticles
Prof. Dr. Francisco M. Goycoolea
One of the main research lines of Goycoolea’s group deals with the study of new strategies to interfere with, and hence inhibit, bacterial cell-cell signaling mechanisms that allow bacteria to control the expression of genes a as function of cell density, a series of processes collectively known as quorum sensing (QS). This is conceived as a key route to exert control on the expression of virulent factors as well as other complex cellular behaviors (e.g. biofilm formation in biological and inert surfaces, sporulation, bioluminescence, pigment and drugs production, among other), several of which are key to their pathogenic capacity. By virtue of this it is expected that less selective pressure is exerted for the development of resistance as compared to that of conventional antibiotic therapy against bacterial pathogens.
The last twelve years or so, have witnessed a remarkable change in the understanding of how bacteria live and function. In this regards, it is now firmly established that bacteria have evolved several mechanisms to facilitate the interaction among them. These interactions extend beyond the species level. One such strategy is the ability to coordinate gene expression in accordance with population density and hence act as a group by QS. QS systems function by means of small, extracellular signal molecules that are known as autoinducers (AIs). In a large number of gram-negative bacteria QS is mediated via a chemically well-defined family of compounds: Acyl-homoserin lactones (AHLs). AHL signaling molecules share in common the following features: are composed by a homoserin lactone (HSL) ring with an acyl chain; the acyl-chain length typically varies from C4 to C18 and many may be modified, most often by a 3-oxo substituent, a 3-hydroxy substituent or a degree of unsaturation. It is known that more than fifteen different types of AHL-related molecules are synthesized by more than seventy species by three different types of enzymes known to synthetize AHLs in vivo, related to LuxI, HdtS and LuxM.
Over the last decade, as the elucidation of the mechanisms underlying QS gained momentum, several strategies have been conceived to block or disrupt QS systems. Given that the virulence factor production of many bacterial pathogens is dependent on QS regulation, disruption of these processes has been accepted to provide two advantages: i) reduced accumulation of virulence factors at the infection site, and ii) the collective power of pathogens being dismantled. These strategies are collectively known as quorum quenching (QQ). There are five known general approaches to QQ: a) Blocking of signal generation by means of potent inhibitors that target various enzymes in the signaling biosynthesis pathway (e.g. by S-adenosyl methionine analogues); b) disturbing signal exchange by inhibition of ABC-type efflux pumps; c) preventing signaling recognition by receptor antagonism with signal analogues; d) signal trapping, for example by use of signal-specific antibodies; e) inactivation of QA signals by use of AHL-degrading enzymes of various classes, namely: AHL-lactonases (NB. hydrolyze the lactone ring moiety in a reversible way), paraoxonases (PONs), AHL-acylases (NB cleave the acyl side chain off the homoserine lactone moiety), AHL-oxoreductases (NB. catalyze the chemical modification of AHLs and not their degradation). In nature these mechanisms are known to operate and whether have they evolved specifically for counteracting bacterial QS is a subject of debate.
The impact and influence of QQ compounds on microbial ecology and pathogen-host interaction is at present an active field of study with a potential still to be fully realized. The potential of nanobiotechnological platforms and approaches that could provide additional advantages to the above-described QQ strategies, is only at its nascent stages. In this regards, general advantages are expected to be at play: 1) A huge surface to volume ratio enabling specific adsorption of autoinducer molecules without inducing a cytotoxic response; 2) controlled and programmed delivery of antagonistic molecules; c) Associate effectively and protect the bioactivity of AHL-degrading enzymes.
Collaborations with:
(WWU);
Prof. Dr. Swamy(UH). External collaborations: Prof. Dr. Susanne Fetzner (WWU) and Prof. Dr. Bodo Philipp (WWU); Prof. Dr. Ioannis Chronakis (Denmark Technical University)
Projects in this direction can be designed around the following ideas
1. "Smart" communicating nanoparticles. We are interested in investigating novel approaches to achieve specific combined functions with nanoparticles of different type that merge a diagnostic (on "transmitter-type" particles) and a targeting drug delivery (on "receiver-type" particles) functions. Localized therapies against bacterial and fungal infections may be treated under this type of approaches. Specific bacterial metabolites such as virulence factors or QS auto-inducers can be used as input signals that can trigger an enzymatic reaction whose product can in turn be targeted by “receiving” particles that could deliver their cargo in a localized site.
2. Surface modified nanoparticles. Molecular imprinting is a well-established chemical synthetic strategy to generate solid polymer-based materials able to recognize specific target analytes. This is the basis for the development of biosensors and affinity matrix. More recently, it has also been possible to imprint “soft” materials such as hydrogel networks including those obtained from chitosan. However, imprinting of biopolymer-based nanoparticles remains a major challenge. Polysaccharide and proteins are ideal natural candidates to design systems with recognition capacity towards molecules known to operate in QS.
A PhD project centered in this challenge will contribute greatly towards this goal.
3. Biophysical theories to describe QS and the effect of different nanobiomaterials. Although attempts have been made to describe the phenomena involved in QS by biophysical and mathematical models, a number of fundamental questions remain unanswered. Is QS a true critical phenomenon, hence, can it be treated by theories that account for this type of phenomena in living and non-living systems? If so, can we make use of such theories to account for and thus better understand the effect of different nanomaterials on the phenomena involved and hence design much more effective QQ systems on a rational basis? Can we create simulation models that describe the dynamics of the interaction between bacterial and nanoparticles? Around these and other questions, it is possible to design an original new PhD project.
