How to kill Pseudomonas—emerging therapies for a challenging pathogen

Abstract

As the number of effective antibiotics dwindled, antibiotic resistance (AR) became a pressing concern. Some Pseudomonas aeruginosa isolates are resistant to all available antibiotics. In this review, we identify the mechanisms that P. aeruginosa uses to evade antibiotics, including intrinsic, acquired, and adaptive resistance. Our review summarizes many different approaches to overcome resistance. Antimicrobial peptides have potential as therapeutics with low levels of resistance evolution. Rationally designed bacteriophage therapy can circumvent and direct evolution of AR and virulence. Vaccines and monoclonal antibodies are highlighted as immune-based treatments targeting specific P. aeruginosa antigens. This review also identifies promising drug combinations, antivirulence therapies, and considerations for new antipseudomonal discovery. Finally, we provide an update on the clinical pipeline for antipseudomonal therapies and recommend future avenues for research.

What Is New in the Anti–Pseudomonas aeruginosa Clinical Development Pipeline Since the 2017 WHO Alert?

“…Because of the fact that P. aeruginosa is an opportunistic bacterium, patients infected with P. aeruginosa are mostly immunocompromised individuals. This makes it difficult to develop a vaccine for these patients ( Yaeger et al., 2021 ). As P. aeruginosa is characterized by its genomic plasticity, drugs or vaccine must be designed to target conserved elements between strains to ensure an optimal efficacy ( Tse et al., 2017 ).…”

“… This table is based on the following references for vaccines ( Merakou et al., 2018 ; Bianconi et al., 2019 ; Theuretzbacher et al., 2020 ; Sainz-Mejías et al., 2020 ; Micoli et al., 2021 ; Antonelli et al., 2021 ), antibodies ( Lakemeyer et al., 2018 ; Theuretzbacher et al., 2020 ; Adlbrecht et al., 2020 ; Yaeger et al., 2021 ; Zurawski and McLendon, 2020 ), polymyxins ( Li, et al., 2019 ; Theuretzbacher et al., 2020 ; Lepak et al., 2020 ), new antibiotics ( WHO, 2021 ; Dickey et al., 2017 ; Tse et al., 2017 ), new combinations of β-lactam/β-lactamase inhibitor ( WHO, 2021 ; Theuretzbacher et al., 2020 ), phages ( Friman et al., 2016 ; Jault et al., 2019 ; Patil et al., 2021 ), iron metabolism disruption ( Zhang et al., 2021 ; Frei et al., 2020 ), anti-biofilm ( Dickey et al., 2017 ), and other anti-virulence factors ( Dickey et al., 2017 ; Theuretzbacher et al., 2020 ). …”

“…With more than 74,000 articles published in PubMed ® in December 2021, knowledge about P. aeruginosa is growing in the fields of its virulence, antibiotic resistance, lifestyle, metabolism, clinical manifestations, clinical or observational studies, health and economic burden, among others. Numerous articles or reviews detail the potential new targets from basic research, the emerging new candidate therapies in early phase, or the pipeline of antibacterial molecules in preclinical and clinical testing and the hope that comes with it ( Burrows, 2018 ; Tümmler, 2019 ; WHO, 2020 ; Theuretzbacher et al., 2020 ; WHO, 2021 ; Yaeger et al., 2021 ). It is difficult to find one’s way through all this data, which is often mixed and rarely dedicated to P. aeruginosa .…”

Virulence Factors of Pseudomonas Aeruginosa and Antivirulence Strategies to Combat Its Drug Resistance

“…Four QS pathways exist in P. aeruginosa , which are las, rhl , iqs , and pqs , utilizing respectively four autoinducers, namely N-(3-oxododecanoyl) -l-HSL (OdDHL), N-butanoyl-L-homoserine lactone (C4-HSL), 2-(2-hydroxyphenyl) -thiazole-4-carbaldehyde (IQS), and 2-heptyl-3-hydroxy-4(1H)-quinolone (PQS) ( Dickey et al., 2017 ). Under certain conditions with adequate bacterial density, the autoinducers will be produced and combine with their receptors to control the transcription of related toxicity genes ( Yaeger et al., 2021 ). QS plays a key role in the virulence of P. aeruginosa , such as regulating the release of multiple virulence factors (including elastase, alkaline protease, exotoxin A, rhamnolipids, pyocyanin and lipase) and promoting the maturation of biofilm as shown by Figure 2 ( O'Donnell et al., 2020 ; Rezzoagli et al., 2020 ).…”

Non-Canonical Host Intracellular Niche Links to New Antimicrobial Resistance Mechanism

“…While vaccines are an active immune-based therapy, the use of antibodies or antisera are common passive immune-based therapies. There are many antibody-based treatments that target various antigens from P. aeruginosa or S. aureus in various stages of clinical trials, as reviewed in [183][184][185]. Compared with antibiotic treatments, antibody-based treatments can be expensive due to the amount of protein required per dose, though there are more cost-effective methods available to treat the host with antibodies, such as using DNA-encoded monoclonal antibodies (DMAbs) that are injected into the host's muscle cells, where the antibodies can be made and then circulated to infections sites.…”