AAC

Using aminoglycoside acetyltransferases and synthetic acyl-coenzyme A derivatives for the development of novel N-acylated antibiotics analogs

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 Obiettivo del progetto (Objective)

'This proposal aims to develop a method that utilizes aminoglycoside acetyltransferases for the in-vitro generation of novel and clinically potent N-acylated aminoglicosides. I propose an efficient and unconventional chemoenzymatic approach for the production of a large variety of N-acylated aminoglycosides. By accomplishing the goals of the proposed research, I will introduce a new and important tool that will provide access to previously unknown and synthetically challenging aminoglycosides. This study may lead to the discovery of new aminoglycosides with superior activity against resistant strains as well explore directions to reduce their toxic side effects. The proposed strategy offers an elegant solution to the following problem: There are no existing general synthetic methodologies for the regio-selective N-acylation of aminoglycosides. Indeed, there are no efficient solutions as to how to chemically modify a specific amine group on an aminoglycoside that contain a series of chemically identical amines. The few existing examples require substantial efforts in both syntheses as well as in cost, and are limited to very specific cases. The three specific aims of the proposed research are: 1) To chemically synthesize coenzyme A (CoA) derivatives as substrates for the chosen AACs. Some CoAs will be utilized to directly produce the desired analogs. Other CoAs will serve as handles for the generation of libraries of new compounds after further derivatization by nucleophilic displacement or click chemistry. 2) We plan to perform biochemical studies on AACs that will target three different positions to be N-acylated on a large number of aminoglycosides. We will study enzyme promiscuity and generate libraries of new compounds using our methodology. 3) We plan to scale-up and test for antibacterial activity some of our novel analogs in search of improved antibacterial activity.'

Introduzione (Teaser)

Bacterial antibiotic resistance is a serious health concern, hampering the clinical outcome of many healthcare interventions. In search of novel antibiotics, European scientists used the very same bacterial enzymes that inactivate traditional antibiotics to produce new ones.

Descrizione progetto (Article)

Aminoglycosides constitute broad-spectrum antibiotics commonly used against many bacterial infections and work by interfering with bacterial protein synthesis.

However, years of clinical use have led to emergence of bacterial resistance to this family of drugs, thereby limiting their efficacy in the clinic.

The mechanism behind this drug resistance involves the evolution of novel enzymes capable of modifying and inactivating aminoglycosides.There are no synthetic methodologies for the selective modification of one particular amine in an aminoglycoside compound.

Scientists of the EU-funded AAC project followed an interesting approach for synthesising novel aminoglycoside-based antibiotics. In particular, they used several aminoglycoside-modifying enzymes that evolved in certain resistant bacterial strains to modify existing aminoglycoside-based drugs.Their approach yielded a series of novel analogues with antimicrobial activity in bacteria with resistance to traditional aminoglycoside antibiotics.

This clearly indicates their ability to overcome several drug resistance pathways.

The same method was exploited for the generation of antibiotics that target bacterial cell membranes.

With special focus on the antibiotic tobramycin, researchers synthesised various aminoglycoside analogues capable of bacterial cell membrane disruption.Collectively, the AAC work presented an interesting concept for overcoming evolutionary mechanisms in bacteria to produce next generation antibiotics.

This novel chemoenzymatic approach opens up new avenues of drug synthesis capable of tackling drug-resistant strains.