Small Molecule Anti-biofilm Agents Developed on the Basis of Mechanistic Understanding of Biofilm Formation

Abstract

Microbial biofilms are the cause of persistent infections associated with various medical implants and distinct body sites such as the urinary tract, lungs, and wounds. Compared with their free living counterparts, bacteria in biofilms display a highly increased resistance to immune system activities and antibiotic treatment. Therefore, biofilm infections are difficult or impossible to treat with our current armory of antibiotics. The challenges associated with biofilm infections have urged researchers to pursue a better understanding of the molecular mechanisms that are involved in the formation and dispersal of biofilms, and this has led to the identification of several steps that could be targeted in order to eradicate these challenging infections. Here we describe mechanisms that are involved in the regulation of biofilm development in Pseudomonas aeruginosa, Escherichia coli, and Acinetobacter baumannii, and provide examples of chemical compounds that have been developed to specifically inhibit these processes. These compounds include (i) pilicides and curlicides which inhibit the initial steps of biofilm formation by E. coli; (ii) compounds that interfere with c-di-GMP signaling in P. aeruginosa and E. coli; and (iii) compounds that inhibit quorum-sensing in P. aeruginosa and A. baumannii. In cases where compound series have a defined molecular target, we focus on elucidating structure activity relationship (SAR) trends within the particular compound series.

Competitive exclusion of uropathogenic E. coli biofilm by Salmonella through matrix inhibition

“…We speculate that the mechanism of inhibition of UPEC matrix or biofilm could be by producing specific polysaccharides that inhibit matrix gene regulation, similar to that reported Valle et al, (2006) or some small molecules, which are sensitive to heat. Interference of these molecules in c-di-GMP signaling cannot be ruled out, as the higher intracellular concentrations of c-di-GMP activate matrix production (Qvortrup et al ., 2019).…”

Synthesis, ADMET Properties, and In Vitro Antimicrobial and Antibiofilm Activity of 5-Nitro-2-thiophenecarbaldehyde N-((E)-(5-Nitrothienyl)methylidene)hydrazone (KTU-286) against Staphylococcus aureus with Defined Resistance Mechanisms

“…Thiophene derivatives were previously shown to have activity directed against biofilm integrity [32]. The study of Chorell et al reports synthesis and characterization of thiophene-bearing compounds with antibiofilm activity.…”

Recent Advances in Surface Nanoengineering for Biofilm Prevention and Control. Part II: Active, Combined Active and Passive, and Smart Bacteria-Responsive Antibiofilm Nanocoatings

“…C-di-GMP is synthesized from two GMP molecules by the enzymes called diguanylate cyclases (DGCs) and is degraded under the hydrolytic activity of two types of specific phosphodiesterase enzymes (PDEs), one that linearizes the molecules converting it into 5’-phosphoguanylyl-(3′→5′)-guanosine (pGpG) and another one that split the molecule into two GMP molecules. Both DGCs and PDEs have conserved catalytic domains as follows Gly-Gly-Asp-Glu-Phe for DGCs and Glu-Ala-Leu/His-Asp—Gly-Tyr-Pro for the PDEs producing pGpG and GMP, respectively [ 59 , 60 ].…”