Biofilms are complex microbial architectures that attach to surfaces and encase microorganisms in a matrix composed of self-produced hydrated extracellular polymeric substances (EPSs). In biofilms, microorganisms become much more resistant to antimicrobial treatments, harsh environmental conditions, and host immunity. Biofilm formation by microbial pathogens greatly enhances survival in hosts and causes chronic infections that result in persistent inflammation and tissue damages. Currently, it is believed over 80% of chronic infectious diseases are mediated by biofilms, and it is known that conventional antibiotic medications are inadequate at eradicating these biofilm-mediated infections. This situation demands new strategies for biofilm-associated infections, and currently, researchers focus on the development of antibiofilm agents that are specific to biofilms, but are nontoxic, because it is believed that this prevents the development of drug resistance. Here, we review the most promising antibiofilm agents undergoing intensive research and development.
In recent decades, many researchers have written numerous articles about microbial biofilms. Biofilm is a complex community of microorganisms and an example of bacterial group behavior. Biofilm is usually considered a sessile mode of life derived from the attached growth of microbes to surfaces, and most biofilms are embedded in self-produced extracellular matrix composed of extracellular polymeric substances (EPSs), such as polysaccharides, extracellular DNAs (eDNA), and proteins. Dispersal, a mode of biofilm detachment indicates active mechanisms that cause individual cells to separate from the biofilm and return to planktonic life. Since biofilm cells are cemented and surrounded by EPSs, dispersal is not simple to do and many researchers are now paying more attention to this active detachment process. Unlike other modes of biofilm detachment such as erosion or sloughing, which are generally considered passive processes, dispersal occurs as a result of complex spatial differentiation and molecular events in biofilm cells in response to various environmental cues, and there are many biological reasons that force bacterial cells to disperse from the biofilms. In this review, we mainly focus on the spatial differentiation of biofilm that is a prerequisite for dispersal, as well as environmental cues and molecular events related to the biofilm dispersal. More specifically, we discuss the dispersal-related phenomena and mechanisms observed in Pseudomonas aeruginosa, an important opportunistic human pathogen and representative model organism for biofilm study.
SummaryIn Pseudomonas aeruginosa, quorum sensing (QS) plays an essential role in pathogenesis and the QS response controls many virulence factors. Using a mealworm, Tenebrio molitor as a host model, we found that Protease IV, a QS-regulated exoprotease of P. aeruginosa functions as a key virulence effector causing the melanization and death of T. molitor larvae. Protease IV was able to degrade zymogens of spätzle processing enzyme (SPE) and SPE-activating enzyme (SAE) without the activation of the antimicrobial peptide (AMP) production. Since SPE and SAE function to activate spätzle, a ligand of Toll receptor in the innate immune system of T. molitor, we suggest that Protease IV may interfere with the activation of the Toll signaling. Independently of the Toll pathway, the melanization response, another innate immunity was still generated, since Protease IV directly converted Tenebrio prophenoloxidase into active phenoloxidase. Protease IV also worked as an important factor in the virulence to brine shrimp and nematode. These results suggest that Protease IV provides P. aeruginosa with a sophisticated way to escape the immune attack of host by interfering with the production of AMPs.
Anthranilate and indole are alternative degradation products of tryptophan, depending on the bacterial species. While indole enhances the biofilm formation of Pseudomonas aeruginosa, we found that anthranilate, the tryptophan degradation product of P. aeruginosa, had an opposite effect on P. aeruginosa biofilm formation, in which anthranilate deteriorated the mushroom structure of biofilm. The anthranilate effect on biofilm formation was differentially exerted depending on the developmental stage and the presence of shear force. Anthranilate slightly accelerated the initial attachment of P. aeruginosa at the early stage of biofilm development and appeared to build more biofilm without shear force. But anthranilate weakened the biofilm structure in the late stage, deteriorating the mushroom structure of biofilms with shear force to make a flat biofilm. To investigate the interplay of anthranilate with indole in biofilm formation, biofilms were cotreated with anthranilate and indole, and the results showed that anthranilate antagonized the biofilm-enhancing effect of indole. Anthranilate was able to deteriorate the preformed biofilm. The effect of anthranilate and indole on biofilm formation was quorum sensing independent. AntR, a regulator of anthranilate-degrading metabolism was synergistically activated by cotreatment with anthranilate and indole, suggesting that indole might enhance biofilm formation by facilitating the degradation of anthranilate. Anthranilate slightly but significantly affected the cyclic diguaniylate (c-di-GMP) level and transcription of major extracellular polysaccharide (Psl, Pel, and alginate) operons. These results suggest that anthranilate may be a promising antibiofilm agent and antagonize the effect of indole on P. aeruginosa biofilm formation. Biofilms are a representative example of bacterial group behavior that provides cells with many biological advantages, such as high infectivity, antibiotic resistance, and strong survivability (1, 2). Currently, most persistent bacterial infections are believed to be associated with antibiotic-resistant biofilms of pathogenic bacteria (3, 4). Pseudomonas aeruginosa, a Gram-negative bacterium, is a ubiquitous and major opportunistic human pathogen. The colonization and biofilm formation of P. aeruginosa cause great losses in many industrial facilities and serious infections such as cystic fibrosis, microbial keratitis, and burn wound infections in humans (4-8). Therefore, control of P. aeruginosa biofilms is a very important issue in medicine, public health, and industry.Anthranilate and indole are both aromatic compounds produced from tryptophan metabolism. In bacteria, tryptophan is metabolized differently depending on the bacterial species, and the key enzyme of this differentiation is tryptophanase, encoded by the tnaA gene (9). Many bacteria, such as Escherichia coli, Haemophilus influenzae, and Vibrio vulnificus, produce indole from tryptophan, since they have tnaA, which converts tryptophan into indole, pyruvate, and ammonia (9, 10). How...
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