Indole And Its Derivatives Potentiates Aminoglycosides Against Gram-positive Bacterium

Persister is a kind of phenotypic mutant bacteria that can tolerate high concentration of antibiotics,often in dormancy state,and survive under lethal concentration of antibiotics.The presence of persister can lead to bacterial antibiotic tolerance,which often leads to chronic infection and recurrent infection.Bacterial phenotype tolerance is an important reason to induce bacterial resistance,and persister has become a serious threat to human and animal health.In order to fight against persister and drug-resistant bacteria and improve the efficacy of traditional antibiotics,it is of great significance to find new fungicides.Here we report that indole and its derivatives potentiates tobramycin to kill stationary-phase S.aureus cells upon hypoionic shock after a short,combined treatment,with its derivative 5-methylindole being the most potent compound tested and with the absence of ions as a prerequisite.Under the condition of hypoionic shock,indole derivatives as adjuvant and tobramycin can kill many types of Staphylococcus aureus.Consistently,this combined treatment also kills various types of S.aureus persister cells as induced by the protonophore CCCP,nutrient shift,or starvation,as well as methicillin-resistant S.aureus(MRSA)cells.Indole derivatives can cooperate with aminoglycoside antibiotics to kill many Gram-positive bacterias,such as Staphylococcus epidermidis,Enterococcus faecalis and Streptococcus pyogenes,among which5-methylindole is the best.However,for Gram-negative bacterias such as E.coli and Shigella,the combination of this method can inhibit the bactericidal effect of antibiotics.Importantly,in the mouse acute skin wound model,5-methylindole can also potentiate tobramycin killing of S.aureus persisters.After long-term treatment,high concentration indole derivatives can be used as fungicides to kill a variety of pathogenic bacteria directly,and can not selectively kill bacteria at platform stage.In addition to S.aureus,other Gram-positive bacteria,such as MRSA,Staphylococcus epidermidis,Enterococcus faecalis,Streptococcus pyogenes and Sarcina rattan,can also be killed directly.At the same time,it has a good bactericidal effect on a variety of Gram-negative pathogens such as Shigella,Klebsiella pneumoniae and Mycobacterium tuberculosis.Under the iso-osmosis condition,indole and its derivatives can also be used as adjuvants to improve the bactericidal efficiency of aminoglycoside antibiotics against S.aureus and MRSA after long-term treatment.Under the iso-osmosis condition,indole and its derivatives mainly increased the uptake of antibiotics by cells to achieve the goal of sterilization.To sum up,through the study of indole and its derivatives,the method to improve the bactericidal efficiency of aminoglycoside antibiotics was found,which provided the basic research for the development of the combination of indole derivatives and antibiotics to achieve the bactericidal purpose.