Staphylococcus aureus is a major cause of nosocomial infections and secretes a diverse spectrum of virulence determinants as well as forms biofilm. The emergence of antibiotic-resistant S. aureus highlights the need for alternative forms of therapeutics other than conventional antibiotics. One route to meet this need is screening small molecule derivatives for potential anti-infective activity. Using a previously optimized C. elegans – S. aureus small molecule screen, we identified a benzimidazole derivative, UM-C162, which rescued nematodes from a S. aureus infection. UM-C162 prevented the formation of biofilm in a dose-dependent manner without interfering with bacterial viability. To examine the effect of UM-C162 on the expression of S. aureus virulence genes, a genome-wide transcriptome analysis was performed on UM-C162-treated pathogen. Our data indicated that the genes associated with biofilm formation, particularly those involved in bacterial attachment, were suppressed in UM-C162-treated bacteria. Additionally, a set of genes encoding vital S. aureus virulence factors were also down-regulated in the presence of UM-C162. Further biochemical analysis validated that UM-C162-mediated disruption of S. aureus hemolysins, proteases and clumping factors production. Collectively, our findings propose that UM-C162 is a promising compound that can be further developed as an anti-virulence agent to control S. aureus infections.

Dithiocarbamates (DTCs) have been used for various applications, including as hardening agents in rubber manufacturing, as fungicide in agriculture, and as medications to treat alcohol misuse disorder. The multi-faceted effects of DTCs rely mainly on metal binding abilities and a high reactivity with thiol groups. Therefore, the list of potential applications is still increasing, exemplified by the US Food and Drug Administration approval of disulfiram (Antabuse) and its metabolite diethyldithiocarbamate in clinical trials against cancer, human immunodeficiency virus, and Lyme disease, as well as new DTC-related compounds that have been synthesized to target diseases with unmet therapeutic needs. In this review, we will discuss the latest progress of DTCs as anti-cancer agents and provide a summary of the mechanisms of action. We will explain the expansion of DTCs' activity in the fields of microbiology, neurology, cardiology, and ophthalmology, thereby providing evidence for the important role and therapeutic potential of DTCs as innovative medical treatments.

A promising approach for treating type 2 diabetes mellitus (T2DM) is to target the Peroxisome Proliferator-Activated Receptor γ (PPARγ) transcription factor, which regulates the expression of proteins critical for T2DM. Mechanisms involved in PPARγ signaling are poorly understood, yet globally increasing T2DM prevalence demands improvements in drug design. Synthetic, nonactivating PPARγ ligands can abolish the phosphorylation of PPARγ at Ser273, a posttranslational modification correlated with obesity and insulin resistance. It is not understood how these ligands prevent phosphorylation, and the lack of experimental mechanistic information can be attributed to previous ambiguity in the field as well as to limitations in experimental approaches; in silico modeling currently provides the only insight into how ligands block Ser273 phosphorylation. The future availability of experimental evidence is critical for clarifying the mechanism by which ligands prevent phosphorylation and should be the priority of future T2DM-focused research. Following this, the properties of ligands that enable them to block phosphorylation can be improved upon to generate ligands tailored for blocking phosphorylation and therefore restoring insulin sensitivity. This would represent a significant step forward for treating T2DM. This review summarizes current knowledge of the roles of PPARγ in T2DM as well as the effects of synthetic ligands on the modulation of these roles. We hypothesize potential factors that contribute to the reduction in recent developments and summarize what has currently been done to shed light on this critical field of research.

Many infectious diseases are associated with multidrug-resistant (MDR) bacteria residing in biofilms that require high antibiotic concentrations. While oral drug delivery is frequently ineffective, topical treatments have the potential to deliver higher drug concentrations to the infection site while reducing systemic side effects. This study determined the antibiofilm activity of a surgical wound gel loaded with the iron chelator deferiprone (Def) and the heme analogue gallium-protoporphyrin (GaPP), alone and in combination with ciprofloxacin. Activity against MDR Staphylococcus aureus , Staphylococcus epidermidis , Pseudomonas aeruginosa , and Acinetobacter johnsonii biofilms was assessed in the colony biofilm and artificial wound model by enumeration of CFU and correlative light/electron microscopy. While Staphylococcus biofilms were equally susceptible to GaPP and Def-GaPP gels (log ₁₀ reduction of 3.8 and 3.7, respectively), the Def-GaPP combination was crucial for significant activity against P. aeruginosa biofilms (log ₁₀ reduction of 1.3 for GaPP and 3.3 for Def-GaPP). When Def-GaPP gel was combined with ciprofloxacin, the efficacy exceeded the activity of the individual compounds. Def-GaPP delivered in a surgical wound gel showed significant antibiofilm activity against different MDR strains and could enhance the gel's wound-healing properties. Moreover, Def-GaPP indicated a potentiation of ciprofloxacin. This antibiofilm strategy has potential for clinical utilization as a therapy for topical biofilm-related infections.

Small colony variants (SCVs) of bacteria like Staphylococcus aureus are characterized by a reduced colony size and are linked to increased antibiotic tolerance and resistance. Their altered expression of virulence factors, slow growing properties and their ability to form biofilms make the eradication of SCVs challenging. In the context of biofilm-related infectious diseases involving S. aureus SCVs, a therapy targeting bacterial iron metabolism was evaluated. The combination of the iron-chelator deferiprone (Def) and the heme-analogue gallium-protoporphyrin (GaPP), in solution and incorporated in a surgical wound gel, was tested for activity against planktonic and sessile SCVs. To this end, the activity of Def-GaPP was assessed against planktonic S. aureus SCVs, as well as against in vitro and in vivo biofilms in the colony biofilm model, an artificial wound model and a Caenorhabditis elegans infection model. While Def alone failed to show substantial antibacterial activity, GaPP and the combination of Def-GaPP demonstrated concentration- and strain-dependent antibacterial properties. Specifically, the Def-GaPP combination significantly reduced the bacterial load in an artificial wound model and increased the survival of S. aureus SCV infected C. elegans. When Def-GaPP were combined with gentamicin or ciprofloxacin, the triple combinations exceeded the antibiofilm activity of the individual compounds in the colony biofilm model. In targeting bacterial iron metabolism, Def-GaPP showed significant activity against planktonic and sessile SCVs. Moreover, Def-GaPP could potentiate the activity of gentamicin and ciprofloxacin. Delivered in a wound healing gel, Def-GaPP showed promise as a new topical strategy against infections with S. aureus SCVs.