Antimicrobials: An update on new strategies to diversify treatment for bacterial infections.

Ninety-five years after Fleming's discovery of penicillin, a bounty of antibiotic compounds have been discovered, modified, or synthesised. Diversification of target sites, improved stability and altered activity spectra have enabled continued antibiotic efficacy, but overwhelming reliance and misuse has fuelled the global spread of antimicrobial resistance (AMR). An estimated 1.27 million deaths were attributable to antibiotic resistant bacteria in 2019, representing a major threat to modern medicine. Although antibiotics remain at the heart of strategies for treatment and control of bacterial diseases, the threat of AMR has reached catastrophic proportions urgently calling for fresh innovation. The last decade has been peppered with ground-breaking developments in genome sequencing, high throughput screening technologies and machine learning. These advances have opened new doors for bioprospecting for novel antimicrobials. They have also enabled more thorough exploration of complex and polymicrobial infections and interactions with the healthy microbiome. Using models of infection that more closely resemble the infection state in vivo, we are now beginning to measure the impacts of antimicrobial therapy on host/microbiota/pathogen interactions. However new approaches are needed for developing and standardising appropriate methods to measure efficacy of novel antimicrobial combinations in these contexts. A battery of promising new antimicrobials is now in various stages of development including co-administered inhibitors, phages, nanoparticles, immunotherapy, anti-biofilm and anti-virulence agents. These novel therapeutics need multidisciplinary collaboration and new ways of thinking to bring them into large scale clinical use.

Emerging strategies to target virulence in Pseudomonas aeruginosa respiratory infections.

Pseudomonas aeruginosa is an opportunistic pathogen that is responsible for infections in people living with chronic respiratory conditions, such as cystic fibrosis (CF) and non-CF bronchiectasis (NCFB). Traditionally, in people with chronic respiratory disorders, P. aeruginosa infection has been managed with a combination of inhaled and intravenous antibiotic therapies. However, due in part to the prolonged use of antibiotics in these people, the emergence of multi-drug resistant P. aeruginosa strains is a growing concern. The development of anti-virulence therapeutics may provide a new means of treating P. aeruginosa lung infections whilst also combatting the AMR crisis, as these agents are presumed to exert reduced pressure for the emergence of drug resistance as compared to antibiotics. However, the pipeline for developing anti-virulence therapeutics is poorly defined, and it is currently unclear as to whether in vivo and in vitro models effectively replicate the complex pulmonary environment sufficiently to enable development and testing of such therapies for future clinical use. Here, we discuss potential targets for P. aeruginosa anti-virulence therapeutics and the effectiveness of the current models used to study them. Focus is given to the difficulty of replicating the virulence gene expression patterns of P. aeruginosa in the CF and NCFB lung under laboratory conditions and to the challenges this poses for anti-virulence therapeutic development.