Amide Isosteres of Oroidin: Assessment of Antibiofilm Activity and C. elegans Toxicity

Abstract

The synthesis and antibiofilm activities of sulfonamide, urea, and thiourea oroidin analogues are described. The most active derivative was able to selectively inhibit P. aeruginosa biofilm development and is also shown to be non-toxic upwards of 1 mM to the development of C. elegans in comparison to other similar isosteric analogues and the natural product oroidin.Bacterial biofilm formation is often described as a developmental process initiated when free floating (planktonic) bacteria adhere to a surface suitable for growth and initiate the formation of a microcolony. 1 Occupation of a biofilm growth state confers to the bacteria a unique set of phenotypic traits which include resistance to microbicides and antibiotics that would often lead to eradication. [2][3][4] In a medical setting, biofilms pose a serious threat to individuals who suffer from a myriad of diseases. Recent estimates have attributed biofilm-associated infections as being responsible for upwards of 75% of microbial infections in the human body. 5 This problem is further exacerbated by the increased spread of antibiotic resistance. Additionally, biofilms are known to infect patients with indwelling medical devices (IMDs a ) such as catheters and heart stents. 6-8 Remediation of biofilm infected IMDs is traditionally accomplished by device removal due to the lack of antibiotic efficacy.As the medical community works towards new approaches aimed at combating the deleterious effects of biofilms, one area that has garnered significant attention is the identification of nonmicrobicidal modulators of biofilm growth and maintenance (Figure 1). 9-13 By not directly killing bacteria, it is postulated that development of resistance to these molecules would be mitigated or significantly impaired. Implementation of remediation therapies which focus on the co-dosing of an antibiofilm modulator with an antibiotic also provides an attractive avenue for treatment. One of the few naturally occurring scaffolds shown to possess non-microbicidal antibiofilm properties are compounds derived from the oroidin class of natural products. Oroidin 5 has been reported to be a moderate inhibitor of Pseudomonas aeruginosa PAO1/ PA14 biofilm growth (PAO1 IC 50 = 190 μM, PA14 IC 50 = 166 μM). 14 *To whom correspondence should be addressed. We have recently begun to focus on the development of methodologies to access oroidin analogues for antibiofilm screening. [15][16][17] Of these approaches, development of conditions for a generic reductive acylation reaction has allowed access to previously unattainable oroidin derivatives through the use of acid chlorides, anhydrides, succinimide esters, and trichloromethylketone pyrroles. 18 In a continued effort, we sought to further apply this approach in generating isosteric analogues possessing sulfonamide, urea and thiourea functionalities to further probe the structure-activity relationships (SAR) of the oroidin family in the context of antibiofilm activity and preliminary toxicity.The Gram-negative γ-proteobacteria Pseu...

Synthesis, cytotoxicity and antimicrobial activity of thiourea derivatives incorporating 3-(trifluoromethyl)phenyl moiety

“…derivatives (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) and N-alkyl- [3-(trifluoromethyl)phenyl]thiourea derivatives (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31) M A N U S C R I P T…”

Novel Pentadecenyl Tetrazole Enhances Susceptibility of Methicillin-Resistant Staphylococcus aureus Biofilms to Gentamicin

“…The combination of gentamicin and SEQ-914 may increase penetration of gentamicin into bacterial cells, resulting in a decrease of CFU. Compounds structurally similar to SEQ-914 have recently been identified and shown to inhibit Pseudomonas aeruginosa biofilms (18,24).…”

“…These infections are costly to treat, often requiring multiple rounds of antibiotics. As a disease, bacterial biofilm infections have an extensive effect on the human body, including skin, bone, ear, sinus, urinary tract, heart, and lung (3,7,20,24,25). Biofilms form on indwelling catheters and other surgically implanted medical devices, necessitating additional surgery to remove or replace the device.…”

5-Benzylidene-4-oxazolidinones potently inhibit biofilm formation in Methicillin-resistant Staphylococcus aureus

“…Melander and co-workers have developed 2-aminoimidazole (2AI) containing small molecules 15 based on the marine derived natural product oroidin 16 (Figure 1) to inhibit biofilm formation and disperse preformed biofilms in a variety of Gram-positive and Gram-negative pathogens. These novel scaffolds have been shown to modulate biofilm formation across multiple species with no appreciable antimicrobial activity 17 . Small molecules that modulate biofilm formation without killing the bacteria are potentially attractive since the development of resistance may be delayed due to decreased selection pressure 18 .…”