Fighting antibiotic resistance—strategies and (pre)clinical developments to find new antibacterials

Abstract

Antibacterial resistance is one of the greatest threats to human health. The development of new therapeutics against bacterial pathogens has slowed drastically since the approvals of the first antibiotics in the early and mid-20 th century. Most of the currently investigated drug leads are modifications of approved antibacterials, many of which are derived from natural products. In this review, we highlight the challenges, advancements and current standing of the clinical and preclinical antibacterial research pipeline. Additionally, we present novel strategies for rejuvenating the discovery process and advocate for renewed and enthusiastic investment in the antibacterial discovery pipeline.

Inhibitors of the Elastase LasB for the treatment of Pseudomonas aeruginosa lung infections

“…Furthermore, the pathogen plays important roles in hospital-acquired and ventilator-associated pneumonia 9,10 , urinary-tract infections 11 , keratitis 12 and wound infections 13 . Taken together, there is an immediate necessity for the development of new anti-infectivesantibiotics with novel mechanisms of action or non-traditional approaches to fight antibiotic resistance; in particular, against Gram-negative pathogens 14 . Recently, significant efforts have been put into the development of 'pathoblockers'agents capable of blocking bacterial virulence by disarming, rather than killing the pathogen.…”

All Roads Lead to Rome: Enhancing the Probability of Target Attainment with Different Pharmacokinetic/Pharmacodynamic Modelling Approaches

“…Although the number of novel antimicrobials has increased recently, most of these novel drugs do not harbor novel modes of action [ 5 , 9 , 10 ]. The persistent lack of innovation has led to fewer newly approved antibiotics in the pipeline than cancer drugs [ 11 ]. Certainly, incentives have to be developed to foster and enable development in this area [ 12 , 13 ].…”

New Genetically Engineered Derivatives of Antibacterial Darobactins Underpin Their Potential for Antibiotic Development

“…In the coming years, increasing antimicrobial resistance (AMR) is expected to induce a rise in the number of deaths of the growing global population from roughly 1.3 million to up to 10 million annually. − In particular, resistant pathogens appear in clinics more often, among other factors in combination with nosocomial infections, leading to increased mortality rates. − Most new antibiotics reaching the development stage are derivatives of known chemical classes with a known target and mode of binding (MoB), resulting in potentially rapid development of cross-resistance. − Thus, the search for antibacterial compounds acting on innovative target sites is urgently required. The recently discovered darobactins are a novel class of antibiotics showing promise for meeting that demand. , Native darobactins found in Photorhabdus khanii are ribosomally produced and post-translationally modified peptides (RiPPs). , They selectively target the outer membrane protein (OMP) BamA, the major component of the BamABCDE (BAM) complex, and inhibit the insertion and folding of OMPs, ultimately resulting in cell lysis. − The target site of darobactins is not addressed by commercially available antibiotics.…”