Beyond investment needed to build a strong pipeline, the Community needs to reinvent medicine with new strategies of development to avoid the disaster. Among 18 drugs of interest in December 2021 antiCdevelopment pipeline explained here, only one new combination of -lactam/-lactamase inhibitor is in phase III trial. Derivatives of existing antibiotics considered as traditional brokers are over-represented. Diverse non-traditional brokers including bacteriophages, iron mimetic/chelator, and anti-virulence factors are significantly represented but regrettably still in early clinical stages. Despite decade of efforts, there is no vaccine currently in clinical development to prevent infections. Studying pipeline antiCsince 2017 up to now shows how to provide a new treatment for patients can be a difficult task. Given the process duration, the clinical pipeline remains unsatisfactory leading best case to the approval of new antibacterial drugs that treat CRPA in several years. Beyond expense needed to build a strong pipeline, the Community needs to reinvent medicine with new strategies of development to avoid the disaster. Among nontraditional brokers, anti-virulence strategy may have the potential through novel and non-killing modes of action to reduce the selective pressure responsible of MDR. (CRPA) were considered critical-priority bacteria (Tacconelli et?al., 2018). Indeed, Carbapenem antibiotics are reserved for the treatment of multi-drug resistant (MDR) bacterial infections, and, when bacteria develop resistance to them, treatment options become extremely limited. is an opportunistic pathogen responsible for both severe acute and chronic infections, and is a significant cause of healthcare-associated infections, particularly in critically ill and immunocompromised patients (Physique?1). Since its first description in wound infections (Gessard, 1882), is now a well-known pathogen. Pathogenesis of is usually mediated by an arsenal of virulence factors: motility, adherence to biotic and abiotic surfaces, secreted toxins also called effectors that are released in the environment or injected into host cells or other bacteria (Physique?2). These effectors are able to PF-04880594 modulate or disrupt host cells signaling pathways, target extracellular matrix, induce tissue damage, and shape the local microbiome by competition (Physique?2). The ability Rabbit Polyclonal to FANCD2 of to form a biofilm?is also a key factor that increases drug resistance and escape from host defense and is responsible PF-04880594 for colony tolerance to disinfectants on medical devices (Mulcahy et?al., 2014; Pang et?al., 2019; Jurado-Martn et?al., 2021). As all these factors contribute to pathogenicity by complementary actions, is characterized by a combinatorial multifactorial virulence. Moreover, multiple mechanisms of antibiotic resistance have been recognized, including intrinsic membrane permeability, drug efflux systems, production of antibiotic-inactivating enzymes, and loss of porin function (Pang et?al., 2019). Finally, the plasticity of its (i) virulence factor gene expression, (ii) antibiotic resistance, and (iii) metabolism in response to selective pressure is one of the most challenging features of allowing the transition from acute to chronic infections. Acute infections are mainly associated with planktonic life style, whereas biofilm plays a major role in persistent infections. This remarkable ability of over-adaptation in a dynamic way allows this pathogen to escape immune system and become MDR or extensively drug resistant (XDR). Once a chronic contamination in the patient is established, is really hard to treat. Open in a separate window Physique?1 Clinical manifestations of infections. Representation of human body site infections and main clinical manifestations of Healthcare-associated infections highlighted in blue illustrate the significant burden of on invasive acts, medical procedures, and device use, resulting in local or systemic complications (Wu et?al., 2011; Dando et?al., 2014; Gahlot et?al., 2014; Elborn, 2016; Durand, 2017; Newman et?al., 2017; Arsovic et?al., 2020; Ramireddy et?al., 2020; Chai and Xu, 2020; Shukla et?al., 2020; Jean et?al., 2020; Montravers et?al., 2020; Cerioli et?al., 2020; Shrestha et?al., 2021; Vieira PF-04880594 et?al., 2016; Hauser and Ozer, 2011). Open in a separate window Physique?2 Key virulence factors of pathogenesis. OMPs, outer membrane proteins; LPS, lipopolysaccharide; ROS, reactive oxygen species; EPS, exopolysaccharides; eDNA, extracellular desoxyribonucleic acid; T4P, type 4 pili; TnSS, type n secretion system; ETA, exotoxin A; PVD, pyoverdine; PCH, pyochelin; PCN, pyocyanin; PG, peptidoglycan; PF-04880594 ECM, extracellular matrix (Alhazmi, 2015; Sana et?al., 2016;.