Activity of Organoboron Compounds against Biofilm-Forming Pathogens

Abstract

Bacteria have evolved and continue to change in response to environmental stressors including antibiotics. Antibiotic resistance and the ability to form biofilms are inextricably linked, requiring the continuous search for alternative compounds to antibiotics that affect biofilm formation. One of the latest drug classes is boron-containing compounds. Over the last several decades, boron has emerged as a prominent element in the field of medicinal chemistry, which has led to an increasing number of boron-containing compounds being considered as potential drugs. The focus of this review is on the developments in boron-containing organic compounds (BOCs) as antimicrobial/anti-biofilm probes and agents.

Keywords: anti-biofilm; antimicrobial; boron-containing compounds; inhibitors of pathogenic bacterial enzymes; multidrug resistance; phenotypic screens.

Figure 1

Introduction to the classes of boron-containing compounds: borane, organoboranes, oxygen-containing boron compounds. To date, fully oxygenated boric acid (BA) is the only naturally occurring form of boron reported.

Figure 2

Boric acid and its linear and cyclic forms as a result of self-assembly and polymerization with additional boric acid molecules.

Figure 3

Representative examples of currently known boron-containing antibiotics forming a Böeseken complex (a complex formed between alcohols/α-hydroxy acids and boron) [51,53].

Figure 4

Structure of AI-2, the universal QS autoinducer: a boron-diester.

Figure 5

Boron-containing compounds in higher plants: Partial structure of Rhamnogalacturonan II (RG-II) with focus on boron–oxygen complex at the center of the RG-II molecule.

Figure 6

Illustrative example of the interconversion of the hybridization of boronic acids in the presence of water.

Figure 7

(A). Equilibrium dissociation and biologically relevant interactions of benzoxaborole in water; (B). Molecular mode of inhibition of vaborbactam, 9, a hemiboronic acid drug by the active site serine.

Figure 8

Examples of boronic acids and their hemiesters targeting β-lactamses: Boronic acids 10–12 and the cyclic hemiester of boronic acid, and FDA-approved Vaborbactam 9 as β-lactamase inhibitors.

Figure 9

Evolution of the hemiboronic acids toward broadening their spectrum as β-lactamase inhibitors (serine- and metallo-β-lactamases) and improving their metabolic stability [97,98,99,100].

Figure 10

Hemiboronic acid 19 VNRX-5133, Taniborbactam), a pan-β-lactamase inhibitor developed based on the binding of the boronic acid 18 as TEM-1 inhibitor [101,102].

Figure 11

Examples of boronic acids targeting microbial defense systems: boronic acid 20 as an inhibitor of the sensor domain of BlaR in MRSA [103].

Figure 12

Structures of oxaboroles: FDA-approved antifungal agent Tavaborole, 21; fluorinated derivatives of 2-formylphenyl boronic acids, 23, 24, designed as antibacterials and antifungals.

Figure 13

Phenyl boronic acids as QS modulators.

Figure 14

3-Pyridine boronic acid-based inhibitors of NorA efflux pump of S. aureus, 29 and 30, demonstrate the best inhibitory activities and potentiate ciprofloxacin against resistant S. aureus by a 4-fold increase at MMC4 of 4 μg/mL.

Figure 15

Boronic acid derivative of N-aryl-oxazolidinones as inhibitor in Gram-positive bacteria.

Figure 16

Oxazaborolidines as AI-2 bioisosteres.

Figure 17

Structures of benzoxazaborines (BONs) and benzodiazaborines (BNNs) and their different chemical characteristics.

Figure 18

Differently substituted aromatic ring-containing diazaborines: 35-sulfonylbenzodiazaborines,with 35a and 35b as the most active compound of this series against Proteus (12.5 μg/mL), Klebsiella (3.12 μg/mL)and Salmonella ( 6.25 μg/mL), Neisseria gonorrhoeae (2–8 μg/mL) and, to a lesser extent, against Escherichia coli (25 μg/mL and Enterobacter (>50 μg/mL) [144]; 38, thieno[2,3-d]diazaborines are slightly more active than 39, thieno[3, 2-d]-diazaborines in general; the 2-alkyl-sulfonyl derivatives of both 38 and 39 have good activities in vitro and in vivo; compound 38a was chosen for further evaluation. Proteus (0.78 μg/mL), Klebsiella (0.39 μg/mL), and Salmonella (0.78 μg/mL), N. gonorrhoeae (1 μg/mL), E. coli (1.56 μg/mL), and Enterobacter (3.12 μg/mL); 40, the furodiazaborines series follow a similar SAR as the 40 series; the methyl-substituted 40a demonstrates good activity: Proteus (3.12 μg/mL), Klebsiella (1.56 μg/mL), and Salmonella (3.12 μg/mL), N. gonorrhoeae (1–8 μg/mL), E. coli (12.5 μg/mL), and Enterobacter (25 μg/mL); the pyrrolodiazaborines 41 are inactive [144]. * means radioactive-labeled compound.

Figure 19

Oligocyclic diazaborine derivatives (42–44) demonstrate very low antimicrobial activity in vitro [144].

Figure 20

2-Acylated 2,3,1-benzodiazaborines and 2-acyl-2,3,1-diazaborine heterocycles with hydration/dehydration abilities. Compounds 45b and 47 demonstrated the best antimicrobial activity against Mycobacterium smegmatis and Escherichia coli, with MIC values of 2–32 (μg/mL) [147].

Figure 21

Structures of benzoxazaborines 48 (BONs) and benzodiazaborines 49 (BNNs) and their different bioactivities [24,140].

Figure 22

Imine–boronic acid crosslink of chitosan: a fragment depicting the amino sugar unit of chitosan reacting with 2-formyl-boronic acid to form an imine IM 27.

Figure 23

Boronic clusters—closo-dodecanoboarate and carborane.

Figure 24

Structures of boron clusters with antimicrobial/anti-biofilm activity.