## 4 Antibiotics Inhibiting Aminoacylation of tRNA
### Inhibition by Trapping tRNA in a LeuRS Editing Domain  
A number of aaRSs, which catalyze the aminoacylation of branched chain amino acids, such as LeuRS, valyl-tRNA synthetase (ValRS) and IleRS, possess an additional proofreading domain called the CP1 domain [77; 78; 79]. This domain is located about \(\sim\)30 A away from the aminoacylation active site and is involved in recognizing and hydrolyzing misacylated amino acids on the 3'-end of the tRNALeu. Recently, a pharmaceutical company (Anacor) used combinatorial screening of a library of organoboron compounds and discovered a novel synthetic compound, AN2690 (Figure 3) that inhibited a fungal LeuRS from the yeast _Saccharomyces cerevisiae_. AN2690 (5-fluoro-1,3 dihydro-1-hydroxy-2, 1-benzoxazole) was found to show broad-spectrum activity with minimum inhibitory concentration (MIC) in the range of 0.5 to 1 \(\upmu\)g/mL. Importantly, when _S. cerevisiae_ colonies resistant to AN2690 were generated, the mutations were all tracked to the _CDC60_ gene, which encodes the cytoplasmic LeuRS [80]. Most interestingly the mutations were found to all be located in the LeuRS editing domain [81]. This observation led to the discovery that AN2690 works by binding to the enzyme's editing domain [80] in a non-competitive manner. Specifically, contacts made with the 2' and 3'-oxygen atoms of the ribose of the 3'-terminal adenosine of tRNA leads to the formation of a stable tRNALeu-AN2690 adduct [80]. This adduct is effectively trapped in the editing domain preventing further rounds of aminoacylation occurring on the enzyme.  
Based on this model, further benzoxaborole derivatives have been synthesized that contain the boronic acid core [82]. Substitution of the oxoboroles at the 3, 6 or 7 positions resulted in derivatives possessing MIC values in the range of 2 to 32 \(\upmu\)M and IC\({}_{50}\) values in the range of 5 to 400 nM. AN2690 was found to be most potent of all the compounds and very effective against fungi, yeast, molds or dermatophytes causing skin infections. AN2690 is specifically effective against _Trichophyton rubrum_ and _Trichophyton mentagrophytes_ the causative agent of onychomycosis, a disease of the human nail bed (an infection that affects approximately 35 million people in the US [83; 84]. Moreover, AN2690 has demonstrated superior activity compared to the already available antibiotics, such as ciclopirox, terbinafine and itraconazole. One of the main advantages AN2690 had over these existing antibiotics is that its small size allows it to easily penetrate and reach the nail bed [85]. Further studies on the physiochemical and pharmacokinetic properties of AN2690 have been carried out. After completion of clinical trials, the FDA has recently approved AN2690 (also called tavaborole) [86]. The new drug is marketed as Kerydin, which is a 5% topical solution of oxaborole for the topical treatment of onychomycosis.  
The use of this boron family of compounds as an antibiotic is not restricted to fungi, as a derivative of oxaborole has been found to be effective against protozoa [87, 88]. These compounds are cyclic boronic esters that are substituted at positions 5, 6 or 7 and are effective against _Trypanosoma brucei_ and _Plasmodium falciparum_ with IC\({}_{50}\) values between 0.07 and 9 \(\mu\)g/mL and 120 nM to 5 \(\mu\)M, respectively [89, 90, 91, 92, 93]. Other compounds with substitution at position 6 by di-substituted aryl or heteroaryl sulfonamides have excitingly been shown to be effective against Gram-positive and Gram-negative bacteria, and also Mycobacterium [82, 84, 86, 94, 95, 96, 97, 98].