Abstract
Antimicrobial resistance (AMR) is a serious threat to public health globally, manifested by the frequent emergence of multidrug resistant pathogens that render current chemotherapy inadequate. Health organizations worldwide have recognized the severity of this crisis and implemented action plans to contain its adverse consequences and prolong the utility of conventional antibiotics. Hence, there is a pressing need for new classes of antibacterial agents with novel modes of action. Quorum sensing (QS), a communication system employed by bacterial populations to coordinate virulence gene expression, is a potential target that has been intensively investigated over the past decade. This Perspective will focus on recent advances in targeting the three main quorum sensing systems ( las, rhl, and pqs) of a major opportunistic human pathogen, Pseudomonas aeruginosa, and will specifically evaluate the medicinal chemistry strategies devised to develop QS inhibitors from a drug discovery perspective.
Highlights
Antimicrobial resistance is a global threat that is imposing an ever increasing burden on public health because of the rapid selection of antibiotic resistance associated with the over- and misuse of antibacterial reagents.[1,2] The withdrawal of most major pharmaceutical companies from antibiotic discovery and their alternative focus on chronic, noncommunicable diseases reflects the difficulties in developing novel antibacterial agents and the enormous cost of bringing new therapeutics to the clinic.In addition, the increasing complexity of the legislation imposed by regulatory bodies and risks associated with antibacterial drug discovery research has restricted further advances in this field.[3,4]Over the past 17 years, only four new classes of antibiotics have been discovered with the majority of Food and Drug Administration (FDA)-approved drugs being based on alterations to existing structures (Figure 1).[4−6]The antibiotic crisis is associated with the appearance of multidrug resistant pathogens, known as “superbugs” that are capable of surviving antibiotic treatment as in the case of the so-called “ESKAPE” panel pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species).[7]According to the World Health Organization (WHO), Pseudomonas aeruginosa represents one of the “critical priority pathogens” that requires urgent attention because of its multidrug resistance (MDR) to a broad spectrum of antibiotics including carbapenems and third generation cephalosporins.[8,9]P. aeruginosa is commonly responsible for lung, skin, eye, wound, blood-borne, and urinary tract infections occurring in both hospitals and the community. 10,11 This Gram-negative bacterium is a common cause of nosocomial infections and a major pathogen in both cystic fibrosis (CF) and immunocom© XXXX American Chemical Society and novel approved antibiotic classes with unprecedented chemical structures and modes of action (green)
P. aeruginosa is commonly responsible for lung, skin, eye, wound, blood-borne, and urinary tract infections occurring in both hospitals and the community. 10,11 This Gram-negative bacterium is a common cause of nosocomial infections and a major pathogen in both cystic fibrosis (CF) and immunocom© XXXX American Chemical Society and novel approved antibiotic classes with unprecedented chemical structures and modes of action
The results indicated that these three drugs can variably inhibit the three quorum sensing systems and reduce biofilm biomass at submillimolar concentrations.[60]
Summary
Antimicrobial resistance is a global threat that is imposing an ever increasing burden on public health because of the rapid selection of antibiotic resistance associated with the over- and misuse of antibacterial reagents.[1,2] The withdrawal of most major pharmaceutical companies from antibiotic discovery and their alternative focus on chronic, noncommunicable diseases reflects the difficulties in developing novel antibacterial agents and the enormous cost of bringing new therapeutics to the clinic.In addition, the increasing complexity of the legislation imposed by regulatory bodies and risks associated with antibacterial drug discovery research has restricted further advances in this field.[3,4]Over the past 17 years, only four new classes of antibiotics have been discovered with the majority of FDA-approved drugs being based on alterations to existing structures (Figure 1).[4−6]The antibiotic crisis is associated with the appearance of multidrug resistant pathogens, known as “superbugs” that are capable of surviving antibiotic treatment as in the case of the so-called “ESKAPE” panel pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species).[7]According to the World Health Organization (WHO), Pseudomonas aeruginosa represents one of the “critical priority pathogens” that requires urgent attention because of its multidrug resistance (MDR) to a broad spectrum of antibiotics including carbapenems and third generation cephalosporins.[8,9]P. aeruginosa is commonly responsible for lung, skin, eye, wound, blood-borne, and urinary tract infections occurring in both hospitals and the community. 10,11 This Gram-negative bacterium is a common cause of nosocomial infections and a major pathogen in both cystic fibrosis (CF) and immunocom© XXXX American Chemical Society and novel approved antibiotic classes with unprecedented chemical structures and modes of action (green). A recent patent described the N-thioacyl homoserine lactone as a las quorum sensing inhibitor with extended effects on pqs and rhl at subinhibitory concentrations; the concentration used was not stated.[65] Another patent reported that the pyrrolidin-2-ol derivative 45 inhibited both LasR and RhlR at concentrations around 400 μM without affecting growth.[66]
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