A Review of Fatty Acid Biosynthesis Enzyme Inhibitors as Promising Antimicrobial Drugs

Abstract

Resistance to antimicrobial drugs is currently a serious threat to human health. Consequently, we are facing an urgent need for new antimicrobial drugs acting with original modes of action. The ubiquitous and widely conserved microbial fatty acid biosynthesis pathway, called FAS-II system, represents a potential target to tackle antimicrobial resistance. This pathway has been extensively studied, and eleven proteins have been described. FabI (or InhA, its homologue in mycobacteria) was considered as a prime target by many teams and is currently the only enzyme with commercial inhibitor drugs: triclosan and isoniazid. Furthermore, afabicin and CG400549, two promising compounds which also target FabI, are in clinical assays to treat Staphylococcus aureus. However, most of the other enzymes are still underexploited targets. This review, after presenting the FAS-II system and its enzymes in Escherichia coli, highlights the reported inhibitors of the system. Their biological activities, main interactions formed with their targets and structure-activity relationships are presented as far as possible.

Keywords: FAS-II inhibitors; antimicrobial resistance; antimicrobials; fatty acid synthase system.

Figure 43

Structure, SAR and representation of main interactions with HpFabZ of flavonoids 48–51 and in vitro activities of lead compounds [103,173,174,176].

Figure 1

Structures of CoA and EcACP (PDB ID 6N3P) [10].

Scheme 1

Schematic of type II fatty acid synthase system. Enzymes in green exist in mycobacteria, while those in blue catalyse the FAS-II system in Gram-negative and -positive bacteria and in Plasmodium spp. Enzymes labelled with * are involved in the FAS-II system of all pathogens. FAS-II is constituted of an initiation step identical in all pathogens (FabD and FabH) and iterated cycles of reduction (FabG or MabA), dehydration (FabA and FabZ or HadAB and HadBC), reduction (FabI, FabK, FabL and FabV or InhA) and condensation (FabB and FabF or KasA and KasB). In the initiation step of mycobacteria, acyl-CoAs are synthesized by FAS-I.

Figure 2

(A) EcFabD apo structure (PDB ID 1MLA). The ferredoxin-like and α/β hydrolase subdomains of EcFabD are coloured in red and blue, respectively. Visual molecular dynamics was used to visualise enzymes and their active sites [32], unless otherwise specified. (B) View of the apo active site of EcFabD (PDB ID 1MLA). This view is focused on the five catalytic residues.

Figure 3

(A) Scheme of the mechanism of the transfer of malonyl moiety from malonyl-CoA to ACP catalysed by FabD in E. coli. (B,C) Views of the active site of EcFabD in which malonyl-CoA was crystallized (PDB ID 2G2Z). They highlight (B) the bidentate salt bridge (blue dots) between the carboxylate moiety of the malonate and the guanidinium group of the Arg117 and (C) hydrogen bonds between the carbonyl of malonate covalently bound to Ser92 and the main-chain amides of Gln11 and Leu93 which form the oxyanion hole (red dots).

Figure 4

(A) EcFabH apo dimer structure (PDB ID 1HN9). One FabH monomer is coloured in blue, the other in red. (B) View of the active site of EcFabH (PDB ID 1HN9). This view is focused on the four catalytic residues.

Figure 5

Scheme of the mechanism of the condensation reactions catalysed by FabH (A) and FabB/F (B) in E. coli. (C) View of the active site of EcFabH-acetyl-CoA structure (PDB ID 1HNH) highlights hydrogen bonds between the carbonyl of acetyl covalently bound to Cys112 and the main-chain amides of Cys112 and Gly306 which form the oxyanion hole (red dots). (D) View of the active site of EcFabB-octanoic acid structure (PDB ID 2BUI) highlights hydrogen bonds between the carbonyl of octanoic acid covalently bound to Cys112 and the main-chain amides of Cys163 and Phe392 which form the oxyanion hole (red dots). (E) View of the active site of EcFabF-dodecanoic acid structure (PDB ID 2GFY) highlights hydrogen bonds between the carbonyl of dodecanoic acid covalently bond to Cys163 and the main-chain amides of Cys163 and Phe400 which form the oxyanion hole (red dots).

Figure 6

Structures, in vitro activities and representation of main interactions with EcFabF/H of platensimycin and platencin [66,69].

Figure 7

Structures, SAR and representation of main interactions with EfFabH of benzoylaminobenzoic acids 1 and 2 and in vitro activities of lead compounds [70].

Figure 8

Structures, SAR and representation of main interactions with EcFabB, EcFabH and MtFabH of TLM and its analogues 3–6 and in vitro activities of lead compounds [41,65,76,77].

Figure 9

Structures, SAR and representation of main interactions with EcFabH of secnidazole derivatives 7 and 8 and in vitro activities and ΔGb of lead compounds [79,80].

Figure 10

Structure, SAR and representation of main interactions with EcFabH of thiazole derivatives 9 and in vitro activities and ΔGb of lead compounds [81].

Figure 11

Structures, SAR and representation of main interactions with SpFabH and EcFabH of indole analogues 10 and 11 and in vitro activities of lead compounds [42].

Figure 12

Structures, SAR and representation of main interactions with EcFabH of chrysin and its analogues 12 and in vitro activities of lead compounds [43].

Figure 13

Structures, SAR and representation of main interactions with MtKasA of GSK3011724A and its derivatives 13–14 and in vitro activities of lead compounds [83,84,85].

Figure 14

Structures and representation of main interactions with EcFabH of SB414011, 15–17 and in vitro activities of lead compounds [36,86].

Figure 15

Structure, SAR and representation of main interactions with EcFabH of Schiff bases 18 and in vitro activities of lead compounds [87].

Figure 16

Structure, representation of main interactions with EcFabB and in vitro activities of cerulenin [41].

Figure 17

(A) EcFabG apo tetramer structure (PDB ID 1I01). The FabG monomers are coloured in blue, red, grey and orange. (B)View of the active site of EcFabG (PDB ID 1I01). This view is focused on the four catalytic residues.

Figure 18

(A) Scheme of the mechanism of the reduction catalysed by EcFabG. (B) View of the active site of EcFabG-NADP⁺ structure (PDB ID 1Q7B) highlights the hydrogen bonds between the hydroxy groups of NADP⁺ and Lys155 as well as the proton relay system (red dots) involving Lys155, Asn110 and four water molecules shown as red spheres.

Figure 19

Structures, representation of main interaction with AbFabG and in vitro activities of CBK261309C and CBK066822 [98].

Figure 20

(A) EcFabA apo-dimer (PDB ID 1MKB) structure. One FabA monomer is coloured in blue, the other in red. (B) EcFabZ trimer of dimers (PDB ID 6N3P) structure. In each dimer, FabZ monomers are coloured in (i) cyan and blue, (ii) pink and red and (iii) orange and yellow. For clarity, the ACPs present in the structure are not shown. (C) View of the active site of EcFabA (PDB ID 1MKB). This view is focused on the two catalytic residues Asp84′ and His70. (D) View of the active site of EcFabZ (PDB ID 6N3P). This view is focused on the two catalytic residues Glu68′ and His54. The crosslinker present in the crystallographic structure was removed for clarity. (E) Tunnel topology of EcFabZ dimer (PDB ID 6N3P). CAVER analyst was used to calculate the tunnel volume indicated as yellow surface. One FabZ monomer is coloured in blue, the other in cyan.

Figure 21

(A) Scheme of the mechanism of the reactions catalysed by EcFabA and EcFabZ. (B) View of the active site of EcFabA (PDB ID 1MKA) in complex with 2-decenoyl-N-acetylcysteamine (NAC). The catalytic His70 is covalently bonded to 2-decenoyl-NAC. (C) View of the active site of EcFabZ in complex with a cross-linker simulating intermediate I (PDB ID 6N3P).

Figure 22

Structure, SAR and representation of main interactions with HpFabZ of Schiff bases 19–22 and in vitro activities of lead compounds [102].

Figure 23

Structure, representation of main interactions with PfFabZ and in vitro activities of NAS compounds [111,113].

Figure 24

(A) EcFabI apo structure (PDB ID 2FHS). The FabI monomers are coloured in blue, red, grey and orange. The AcpPs present in the structure were removed for clarity. The orange star symbolises the major portal (MajP), and the blue arrow represents the entry of the minor portal (MinP). (B) View of the active site of EcFabI (PDB ID 2FHS). This view is focused on the two catalytic residues Tyr156 and Lys163.

Figure 25

(A) Scheme of the mechanism of the reduction catalysed by EcFabI. (B) View of the active site of EcFabI-NAD⁺ structure (PDB ID 1DFI) highlights the hydrogen bonds between the hydroxy groups of NAD⁺ and Lys163 (red dots).

Figure 26

Structure, SAR and representation of main interactions with EcFabI and BaFabI of triclosan and its analogues 23 and in vitro activities of lead compounds [131,132,133,134,144,145].

Figure 27

Structure, SAR and representation of the main interactions with SaFabI of triclosan derivatives 24–26 and in vitro activities of lead compounds [146].

Figure 28

Structure, SAR and representation of main interactions with SaFabI of coumarin derivatives 27–28 and in vitro activities of lead compounds [147,148].

Figure 29

Structure, SAR and representation of main interactions with PfFabI of triclosan derivatives 29–31 and in vitro activities of lead compounds [132].

Figure 30

Structure, representation of the main interactions with MtInhA and in vitro activities of INH and its active form bound to NADH [7,47,126].

Figure 31

Structure and SAR of 32–33 and in vitro activities of lead compounds [145].

Figure 32

Structure and SAR of 4-pyridone derivatives 34 and 35 and in vitro activities [155,156].

Figure 33

Structure, SAR and representation of main interactions with YpFabV of CG400549 and 36–38 and in vitro activities of lead compounds [17,157].

Figure 34

Structure, SAR and representation of main interactions with SpFabK of phenylimidazole derivatives 39–41 and in vitro activities of lead compounds [158].

Figure 35

Structure, SAR and representation of main interactions with EcFabI of imidazoles 42 and in vitro activities of lead compound [159].

Figure 36

Structure, SAR and representation of main interactions with EcFabI of 43–46 and in vitro activities of lead compounds [128].

Figure 37

Structure, SAR and representation of main interactions with EcFabI of 47–50 and in vitro activities of lead compounds [160,161].

Figure 38

Structure, interactions with SaFabI and EcFabI and in vitro activity of afabicin dephosphono and its analogues [115,163,164].

Figure 39

Structure and in vitro activities of verrulactones A and B [167,168].

Figure 40

Structure and in vitro activities of Aquastatin A [169].

Figure 41

Structure, SAR and in vitro activities of panosialins A, B, wA and wB [170].

Figure 42

Structures and inhibitory activities of atromentin and leucomelone [171].