Current landscape in the discovery of novel antibacterial agents

Abstract

Background: Standard treatments against bacterial infections are becoming ineffective due to the rise of antibacterial resistance worldwide. Classical approaches to develop new antibacterial agents are not sufficient to fulfil the current pipeline, therefore new strategies are currently being conducted devised in the field of antibacterial discovery. Objectives: The objective of this narrative review is to compile the most successful strategies in which research on drug discovery within the antibacterial context is currently ongoing. Sources: Peer-reviewed publications from the MEDLINE database with robust data addressing the discovery of new antibacterial agents in the current pipeline have been selected. Content: Several strategies to discovery new antibacterial are described in this review, such as: i. Derivatives of known antibacterial agents. The activity of a known antimicrobial agent can be improved through two strategies: a) Modification of the original chemical structure of an antimicrobial agent which circumvents antibacterial resistant mechanisms, and b) Development of a compound that inhibits the mechanisms of resistance to an antibacterial agent; ii. New antibacterial agents targeting new proteins; iii. Inhibitors of virulence factors; iv. Nanoparticles; v. Antimicrobial peptides (AMPs) and peptidomimetics; vi. Phage therapy and enzybiotics, and vii. Antisense oligonucleotides. Implications: This review intends to provide a positive message affirming that several different strategies to design new antibacterial agents are currently being developed, and we are therefore confident that in the near future some of the most promising approaches will come to fruition.

An Update on Antimicrobial Peptides (AMPs) and Their Delivery Strategies for Wound Infections

“…Omiganan (indolicidin derived; MBI-226) failed during phase III due to catheter-related infections [10]. XMP-629 was used to treat impetigo and acne rosacea, and Murepavadin (POL7080) [72], a protegrin analogue used to treat ventilator-associated bacterial pneumonia, was halted recently in phase III. These failures were attributed to the lack of significant efficacy compared to other antibacterial drugs or to multiple side effects [23].…”

“…However, these nanosystems contain Au or Ag, which are known to be poorly biocompatible and non-biodegradable over long periods of time, and their elimination from the human body is not completely understood [3,176]. AgNPs compounds show very promising results in vitro, although their application can be hindered due to their toxicity seen in vivo [69,72]. As for Au, very recently, Balfourier et al investigated AuNPs and concluded that Au can be metabolized by mammalian cells.…”

Bioactive Metabolites of Marine Origin Have Unusual Effects on Model Membrane Systems

“…The scientific and commercial interest for finding new compounds with antibiotic and antineoplastic properties has increased in the last two decades as antibiotic and multi-drug resistance in cancer remains a pressing societal challenge [1][2][3][4]. Approaches to meet this challenge include producing analogs of existing compounds and designing new compounds that interfere with the cellular processes that are required for proliferation [1,5].…”

“…These analogs simplified the side chains and also involved modifications in the adenine ring [15][16][17][18][19][20]. Data for analogs (2)(3)(4) are shown in Table 1. We have also previously reported the first total synthesis of a malonganenone J (5) [21] and evaluated its biological activity (Table 1).…”

“…It has also been documented that transferring oleic acid to the cell membrane using protein fatty-acid complexes, liprotides, cause cancer cell death through disruptive effects on the membranes [34,35]. These phenomena, along with recent evidence indicating that even small changes to the composition of lipid systems may have a pronounced effect on their phase behavior [29,[36][37][38], prompted us to investigate malonganone J, agelasine D, and agelasine analogs using hydrated dioleoylphosphatidylcholine (DOPC) and dioleoylphosphatidylethanolamine (DOPE) model lipid systems doped with these compounds (1)(2)(3)(4)(5).…”