Antibacterial Prodrugs to Overcome Bacterial Antimicrobial Resistance

Abstract

Antimicrobial resistance (AMR) is an increasingly concerning phenomenon that requires urgent attention because it poses a threat to human and animal health. Bacteria undergo continuous evolution, acquiring novel resistance mechanisms in addition to their intrinsic ones. Multidrug-resistant and extensively drug-resistant bacterial strains are rapidly emerging, and it is expected that bacterial AMR will claim the lives of 10 million people annually by 2050. Consequently, the urgent need for the development of new therapeutic agents with new modes of action is evident. The antibacterial prodrug approach, a strategy that includes drug repurposing and derivatization, integration of nanotechnology, and exploration of natural products, is highlighted in this review. Thus, this publication aims at compiling the most pertinent research in the field, spanning from 2021 to 2023, offering the reader a comprehensive insight into the AMR phenomenon and new strategies to overcome it.

Keywords: antibacterial prodrugs; antimicrobial resistance; gram-negative bacteria; gram-positive bacteria; prodrug development; tuberculosis.

Figure 1

Structure of isoniazid (1), INH-HB (2), and β-CD (3) [16,17,18].

Figure 2

Structure of ethionamide (4) and SMARt751 (5) [19].

Figure 3

Structure of SPR720 (6) [20].

Figure 4

Structure of nNF prodrugs 7 and 8 [21].

Figure 5

Structure of aminopyrrolidine (9), aminomethylpyrrolidine (10) ciprofloxacin (11), and biofilm-targeted prodrugs 12–15. P. aeruginosa lectin probes, cleavable peptide linkers and antibiotic cargos are highlighted in blue, green and pink, respectively [22].

Figure 6

Structure of moxifloxacin (16), N-moxi (17), and C-moxi (18) [23].

Figure 7

Structure of ruthenium-catalyst 19 and siderophore-linked catalysts 20 and 21 [23].

Figure 8

Structure of TBP-PI-HBR (22), ceftibuten (23), and avibactam (24) [24,25,26,27,28,29,30].

Figure 9

Structure of rifabutin (25) and rifabutin-based prodrugs 26–28 [31].

Figure 10

Structure of tobramycin (29) and azithromycin (30) [32].

Scheme 1

Illustration of the self-assembly of DPNA (31) and of the formation HSA@DPNA (32) (inspired by the original illustration in [32]).

Figure 11

Structure of colistin methanesulfonate (33) and pEt_20 (34). Colistin moiety is highlighted in pink [34].

Scheme 2

Illustration of the self-assembly of CMS-pEt_20 (35) (inspired by the original illustration in [34]).

Figure 12

Structure of cisplatin (36), enterobactin (37), and the prodrugs l-EP (38) and d-EP (39) [35].

Figure 13

Structure of zidovudine (40) and zidovudine-based prodrugs 41 and 42 [36].

Scheme 3

General mechanism of activation of zidovudine prodrugs by β-lactamase enzymes, releasing zidovudine (40) [36].

Figure 14

Structure of oxacillin (43) and TXA709 (44) [37].

Figure 15

Structure of marine phenazine (45), carbonate-linked HP prodrugs 46–49, and nitroarene-based HP prodrug 50 [38,39].

Scheme 4

Mechanism of activation of HP-prodrugs 46 and 50 through intermediates 51 and 52, respectively, into the active HP (53) [38,39].

Figure 16

Structure of vancomycin (54) [41].

Scheme 5

Structure and mechanism of self-assembly of the PEG-Schiff-Van conjugate (55) into PEG-Schif-Van@Van (56) nanoparticles. Vancomycin moiety is highlighted in purple and the pH-sensitive bond in green (inspired by the original illustration in [41]).

Figure 17

Structure of PEG-b-PCAE (57), curcumin (58), PEG₆₀₀-Curc complex (59), and protocatechuic acid (60) [42,43,44].

Figure 18

Structure of tedizolid phosphate (61) [45].

Figure 19

Structure of capecitabine (62) [46] and nucleoside-based prodrugs 63 and 64 [47].

Figure 20

Structure of florfenicol-polyarginine conjugates 65–67. Florfenicol moiety is highlighted in blue [48].

Scheme 6

Illustration of the structure of HiZP (68) (inspired by the original illustration in [49]).

Figure 21

Structure of compound 69 synthesized by Weng et al. [50].

Scheme 7

Illustration of the micelles formed by compound 69 (inspired by the original illustration in [50]).

Figure 22

Structure of the cinnamaldehyde prodrug (70) [52].

Figure 23

Structure of diacerein (71), rhein (72), Bet6-IL (73), and Carn9-IL (74) [53].