Transcriptomic Analysis of the Activity of a Novel Polymyxin against Staphylococcus aureus

Abstract

S. aureus is currently one of the most pervasive multidrug-resistant pathogens and commonly causes nosocomial infections. Clinicians are faced with a dwindling armamentarium to treat infections caused by S. aureus, as resistance develops to current antibiotics. This accentuates the urgent need for antimicrobial drug discovery. In the present study, we characterized the global gene expression profile of S. aureus treated with FADDI-019, a novel synthetic polymyxin analogue. In contrast to the concentration-dependent killing and rapid regrowth in Gram-negative bacteria treated with polymyxin B and colistin, FADDI-019 killed S. aureus progressively without regrowth at 24 h. Notably, FADDI-019 activated several vancomycin resistance genes and significantly downregulated the expression of a number of virulence determinants and enterotoxin genes. A synergistic combination with sulfamethoxazole was predicted by pathway analysis and demonstrated experimentally. This is the first study revealing the transcriptomics of S. aureus treated with a novel synthetic polymyxin analog.

Polymyxin B in combination with meropenem against carbapenemase-producing Klebsiella pneumoniae: pharmacodynamics and morphological changes

“…A standard procedure was followed for SEM analysis [22] with minor modifications. Briefly, bacterial broth cultures in log phase (20 mL) at ca.…”

Activation of metabolic and stress responses during subtoxic expression of the type I toxin hok in Erwinia amylovora

“…Alkaline conditions, in which the PMF is dissipated to maintain the inverted pH gradient, results in upregulation of ATP synthases and downregulation of chemotaxis genes in E. coli (64). The membrane-targeting antibiotic polymyxin strongly upregulates metabolic pathways while repressing key virulence factor genes in Staphylococcus aureus (22). Exposure to the membrane destabilizer 1-(1naphthylmethyl)-piperazine causes upregulation of many stress response genes, including dnaJ, dnaK, and pspABCD (26).…”

“…Though the effects vary in different bacteria, perturbation of the cell membrane seems to cause shared consequences in activating stress responses and downregulating genes that encode energy consuming machinery (22)(23)(24)(25)(26). Addition of polymyxin, an antibiotic that causes formation of membrane pores and cell death in bacteria, caused increased expression of genes associated with vancomycin resistance and decreased expression of virulence factor-related genes in Staphylococcus aureus (22); exposure of Klebsiella pneumoniae to 1-(1-Naphthylmethyl)-piperazine depolarized the membrane PMF yet upregulated many envelope stress response genes (26). Still, it is not known whether endogenous pore-forming toxins also trigger stress response or in uence the expression of virulence genes.…”

Identification of Genes Regulating Cell Death inStaphylococcus aureus

“…FolD is a bifunctional protein that allows the production of continuous tetrahydrofolate which is a key metabolite for amino acid and nucleic acid biosynthesis [38]. The catalytic step of FolD is a checkpoint that regulates folate production [39]. As such, a mutant of folD may disturb the negative feedback of folate synthesis and continuously produce important metabolites and nucleotides for continued survival under stressed conditions.…”