Strategies to Improve the Potency of Oxazolidinones towards Bacterial Biofilms

Abstract

Biofilms are part of the natural lifecycle of bacteria and are known to cause chronic infections that are difficult to treat. Most antibiotics are developed and tested against bacteria in the planktonic state and are ineffective against bacterial biofilms. The oxazolidinones, including the last resort drug linezolid, are one of the main classes of synthetic antibiotics progressed to clinical use in the last 50 years. They have a unique mechanism of action and only develop low levels of resistance in the clinical setting. With the aim of providing insight into strategies to design more potent antibiotic compounds with activity against bacterial biofilms, we review the biofilm activity of clinically approved oxazolidinones and report on structural modifications to oxazolidinones and their delivery systems which lead to enhanced anti-biofilm activity.

Keywords: Antibiotics; Biofilm; Drug Design; Drug delivery; Oxazolidinone.

Figure 1

The five stages of biofilm formation depicted pictorally and with microscope magnification. Reproduced with permission. Ref. [24] Copyright 2020, Springer Nature.

Figure 2

Linezolid's mode of action: a) During the translation of mRNA the ribosome moves along the mRNA, reading codon by codon, to synthesise a chain of amino acids which then fold into protein; b) Linezolid binds to the A site on the 50S ribosome preventing tRNA from binding and therefore inhibiting protein synthesis.

Figure 3

Chemical structures of linezolid (1), tedizolid (2) and tedizolid phosphate (3).

Figure 4

The chemical structure of linezolid (1) and its structure‐activity relationships.

Figure 5

Chemical structures of RBx 11760 (4) and FYL 67 (5) which include biaryl ring systems.

Figure 6

SEM images of S. aureus biofilms formed in vivo on catheters. a) S. aureus ATCC 25923 biofilms before treatment with FYL 67 (5), b) S. aureus ATCC 25923 biofilms before treatment with linezolid (1), c) eradication of biofilm after treatment with FYL 67 and d) after treatment with linezolid (1). Reproduced with permission. Ref. [134] Copyright 2014, Oxford Academic.

Figure 7

Chemical structures of ranbezolid (6) and radezolid (7).

Figure 8

The chemical structure of an AHL (8), a quorum sensing signalling molecule (9), a bioisostere of an AHL (10) and the analogue YXL‐13 (11).

Figure 9

Biologically active 4‐oxazolidinones found in nature: synoxazolidinone A (12) and lipoxazolidinone A (13), along with analogues 14, 15 and JJM‐ox‐3‐70 (16) which display antibiofilm activity.

Figure 10

Linezolid loaded polymer nanoparticles (LPN) can treat biofilms and intracellular biofilms associated with osteomyelitis infections. (A) Eradication of intracellular MRSA (USA3000114) biofilms grown in osteoblasts (MC3T3E1) is enhanced by loading the nanoparticles with linezolid. (B) Linezolid loaded LPNs are effective against MRSA biofilms grown in a microplate assay, biofilm retention determined by CV assay. (C) Confocal laser scanning microscopy images of osteoblast cells (nuclei: blue, membranes: green) treated with linezolid LPNs (red). Adapted with permission. Ref. [135] Copyright 2020, Elsevier.

Figure 11

Point‐of‐care antibiotic coatings that can be applied using a simple process initiated by light. (A) Polyallyl mercaptan and four arm mercaptopolyethylene glycol stars were crosslinked using UV light and a photocatalyst to create antibiotic loaded coatings on medical devices such as titanium pins. (B) Efficacy of coatings on titanium pins, loaded with different antibiotics, was evaluated using a microtiter plate assay and a bioluminescent strain of S. auereus, with (C) quantified results over time. Adapted with permission. Creative Commons CC BY https://creativecommons.org/licenses/by/4.0/.