The growing emergence of antimicrobial resistance represents a global problem that not only influences healthcare systems but also has grave implications for political and economic processes. As the discovery of novel antimicrobial agents is lagging, one of the solutions is innovative therapeutic options that would expand our armamentarium against this hazard. Compounds of interest in many such studies are antimicrobial peptides (AMPs), which actually represent the host’s first line of defense against pathogens and are involved in innate immunity. They have a broad range of antimicrobial activity against Gram-negative and Gram-positive bacteria, fungi, and viruses, with specific mechanisms of action utilized by different AMPs. Coupled with a lower propensity for resistance development, it is becoming clear that AMPs can be seen as emerging and very promising candidates for more pervasive usage in the treatment of infectious diseases. However, their use in quotidian clinical practice is not without challenges. In this review, we aimed to summarize state-of-the-art evidence on the structure and mechanisms of action of AMPs, as well as to provide detailed information on their antimicrobial activity. We also aimed to present contemporary evidence of clinical trials and application of AMPs and highlight their use beyond infectious diseases and potential challenges that may arise with their increasing availability.

/pdf/antimicrobial-peptides-mechanisms-of-action-antimicrobial-1eqxdbpj.pdf

Antimicrobial Peptides—Mechanisms of Action, Antimicrobial Effects and Clinical Applications

The need for new antibacterial drugs to treat the increasing global prevalence of drug-resistant bacterial infections has clearly attracted global attention, with a range of existing and upcoming funding, policy, and legislative initiatives designed to revive antibacterial R&D. It is essential to assess whether these programs are having any real-world impact and this review continues our systematic analyses that began in 2011. Direct-acting antibacterials (47), non-traditional small molecule antibacterials (5), and β-lactam/β-lactamase inhibitor combinations (10) under clinical development as of December 2022 are described, as are the three antibacterial drugs launched since 2020. Encouragingly, the increased number of early-stage clinical candidates observed in the 2019 review increased in 2022, although the number of first-time drug approvals from 2020 to 2022 was disappointingly low. It will be critical to monitor how many Phase-I and -II candidates move into Phase-III and beyond in the next few years. There was also an enhanced presence of novel antibacterial pharmacophores in early-stage trials, and at least 18 of the 26 phase-I candidates were targeted to treat Gram-negative bacteria infections. Despite the promising early-stage antibacterial pipeline, it is essential to maintain funding for antibacterial R&D and to ensure that plans to address late-stage pipeline issues succeed. 

/pdf/antibiotics-in-the-clinical-pipeline-as-of-december-2022-16jjeayo.pdf

Antibiotics in the clinical pipeline as of December 2022

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‐20th 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.

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

Abstract Polymyxins are last-resort antibiotics with potent activity against multi-drug resistant pathogens. They interact with lipopolysaccharide (LPS) in bacterial membranes, but mechanistic details at the molecular level remain unclear. Here, we characterize the interaction of polymyxins with native, LPS-containing outer membrane patches of Escherichia coli by high-resolution atomic force microscopy imaging, along with structural and biochemical assays. We find that polymyxins arrange LPS into hexagonal assemblies to form crystalline structures. Formation of the crystalline structures is correlated with the antibiotic activity, and absent in polymyxin-resistant strains. Crystal lattice parameters alter with variations of the LPS and polymyxin molecules. Quantitative measurements show that the crystalline structures decrease membrane thickness and increase membrane area as well as stiffness. Together, these findings suggest the formation of rigid LPS–polymyxin crystals and subsequent membrane disruption as the mechanism of polymyxin action and provide a benchmark for optimization and de novo design of LPS-targeting antimicrobials. 

/pdf/antibiotic-polymyxin-arranges-lipopolysaccharide-into-2owk08fd.pdf

Antibiotic polymyxin arranges lipopolysaccharide into crystalline structures to solidify the bacterial membrane

Alternative therapeutic strategies to treat antibiotic-resistant pathogens.

The emergence of multidrug-resistant (MDR) Gram-negative pathogens is an urgent global medical challenge. The old polymyxin lipopeptide antibiotics (polymyxin B and colistin) are often the only therapeutic option due to resistance to all other classes of antibiotics and the lean antibiotic drug development pipeline. However, polymyxin B and colistin suffer from major issues in safety (dose-limiting nephrotoxicity, acute toxicity), pharmacokinetics (poor exposure in the lungs) and efficacy (negligible activity against pulmonary infections) that have severely limited their clinical utility. Here we employ chemical biology to systematically optimize multiple non-conserved positions in the polymyxin scaffold, and successfully disconnect the therapeutic efficacy from the toxicity to develop a new synthetic lipopeptide, structurally and pharmacologically distinct from polymyxin B and colistin. This resulted in the clinical candidate F365 (QPX9003) with superior safety and efficacy against lung infections caused by top-priority MDR pathogens Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. 

/pdf/a-synthetic-lipopeptide-targeting-top-priority-multidrug-dx5anm8m.pdf

A synthetic lipopeptide targeting top-priority multidrug-resistant Gram-negative pathogens


 
 
 Central nervous system (CNS) infections caused by KPC-producing Enterobacterales and difficult-to-treat resistant (DTR)-Pseudomonas aeruginosa represent a formidable clinical challenge. Antimicrobial regimens that efficiently penetrate the cerebrospinal fluid (CSF) and achieve sufficient concentrations associated with microbiologic and clinical cure are limited. We evaluated therapy with ceftazidime-avibactam (CAZ-AVI) in order to guide precise dosing in the treatment of CNS infections.
 
 
 
 Therapeutic drug monitoring (TDM) was performed in three patients with healthcare-associated ventriculitis & meningitis (HAVM) using CAZ-AVI 2.5 g infused intravenously every 8 hours as standard and extended infusion. Simultaneous CSF and plasma samples were obtained throughout the dosing interval in each patient. Concentrations of ceftazidime (CAZ) and avibactam (AVI) were determined by liquid chromatography/mass spectrometry (LC/MS).
 
 
 
 Bacterial identification revealed KPC-producing Klebsiella pneumoniae (KPC-Kp), difficult-to-treat resistant (DTR) Pseudomonas aeruginosa, and KPC-producing Enterobacter cloacae (KPC-Ent.c). All isolates were resistant to carbapenems. The minimum inhibitory concentrations (MIC) of CAZ-AVI were 0.25/4, 4/4, and 0.25/4 μg/ml, respectively. CAZ and AVI concentrations were determined in CSF samples ranging from 29.0 to 15.0 µg/ml (CAZ component) and 4.20 to 0.92 µg/ml (AVI Component), respectively. AVI achieved concentrations ≥1 µg/ml in 11 out of 12 CSF samples collected throughout the dosing interval. Clinical and microbiologic cure were attained in all patients.
 
 
 
 Post-infusion concentrations of CAZ-AVI were measured in plasma and CSF samples obtained from three patients with complicated CNS infections caused by antimicrobial resistant isolates. The measured concentrations revealed that standard CAZ and AVI exposures sufficiently attained values correlating to 50% fT > MIC which are associated with efficient bacterial killing.


Utilizing ceftazidime/avibactam therapeutic drug monitoring (TDM) in the treatment of neurosurgical meningitis caused by difficult-to-treat resistant (DTR) Pseudomonas aeruginosa and KPC-producing Enterobacterales

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A synthetic lipopeptide targeting top-priority multidrug-resistant Gram-negative pathogens

Utilizing ceftazidime/avibactam therapeutic drug monitoring (TDM) in the treatment of neurosurgical meningitis caused by difficult-to-treat resistant (DTR) Pseudomonas aeruginosa and KPC-producing Enterobacterales