Design, synthesis, and evaluation of novel antimicrobials for the eradication of biofilms

Abstract

The majority of microorganisms live in association with surfaces as biofilms. Biofilm communities are encased in a robust, extracellular matrix that reduces their susceptibility to antimicrobial agents. This poses a health concern due to the potential for pathogenic bacteria to cause serious infections. For example, hospital-acquired infections are among the top ten leading causes of death in the U.S. and are responsible for nearly 23,000 deaths per year. The goal of my research is to develop efficient antimicrobial agents capable of eradicating biofilms. In this project, I have focused on three different derivatizations of small, phenolic compounds in effort to increase efficacy towards biofilms. An initial study compared the potency of small, naturally occurring phenols and their corresponding allyl, propyl, and methallyl derivatives against bacteria. This study showed that in parent and derivative pairs potency increased towards free floating cells but decreased towards biofilms. This illustrated the importance of evaluating antimicrobial efficacy toward biofilms when the bacteria they intend to treat has the propensity to form biofilms. This was in contrast to a second studyishowing that trichloromethylsulfenate ester derivatives generally increased potency towards both biofilms and planktonic cells. In a third study, we found that iminodiacetoxy-methylester (AM) appendages increase potency towards planktonic cells and biofilms. AM appendages are ester groups that are employed as part of a prodrug design. Prodrugs are biologically inactive compounds until metabolized. Ester groups are commonly used in prodrug intracellular dyes, where, once inside the cell, ester groups are cleaved enzymatically, resulting in a negatively charged dye that is retained in the cell. Similarly, after the cleavage event, the AM antimicrobial compound will concentrate within the cell. This design serves two functions to increase potency: increasing permeability towards the biofilm matrix and achieving cellular retention. We have shown that the efficacy of antimicrobial agents towards biofilms can be increased through this strategic design. This class of prodrugs presents a wide array of potential applications, from controlling hospital-acquired infections to incorporation into household cleaning products and addresses the need for novel treatments of pathogenic bacteria.