Table 1 Comparison of antitubercular antibiotics to identify shortest biosynthetic pathways with biologically available precursors.

Isoniazid

1st

Chemo-therapeutic¹¹

0.02–0.2^18,19,20,21

1¹¹

2¹¹

Inhibitory mutations of peroxidase genes (katG, ahpC)^22,23, mutations of the promoter region of a key fatty acid synthesis enzyme gene (inhA)^22,24, and facilitatory mutations in the NADH dehydrogenase gene (ndh)^24,25

Rifamycin SV^†

1st

Antibiotic¹¹

Rifampicin: 0.05–0.53^{8,9,10,11,12,13,14,15,16,17,18,19,20,21,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46}

Rifapentine: 0.015–0.6 ^20,21,21,45

27⁴⁷

7^47,48

Rifampicin: Mutations that change the binding affinity of the b subunit of bacterial RNA polymerase for rifampicin (rpoB)^49,50,51

Rifapentine: Mutations of rpoB, often the same as those that confer rifampicin resistance^49,51

Pyrazinamide

1st

Chemo-therapeutic¹¹

12.5–20^20,52,53

5¹¹

6¹¹

Inhibitory mutations of the pyrazinamidase gene (pncA)^54,55 and mutations that change the binding affinities of ribosomal protein S1 (rpsA)^54,56 and aspartate l-decarboxylase (panD) for pyrazinamide^54,57

Ethambutol

1st

Chemo-therapeutic¹¹

0.5–2.0 ^{19,20,21,58,59,60}

3¹¹

5¹¹

Facilitatory mutations in a gene cluster critical for mycobacterial cell wall synthesis (embCAB)^61,62 and those in a gene that encodes a protein (DPA) that competitively binds to ethambutol (ubiA)^63,64

Cycloserine

2nd

Antibiotic¹¹

10–50^21,60,65

6¹⁴

2¹⁴

Mutations causing the overexpression of alanine racemase (alr)^16,66,67 and loss-of-function mutations of the L-alanine dehydrogenase gene (ald)⁶⁸

Ethionamide

2nd

Chemo-therapeutic¹¹

0.25–1.25 ^20,21,60

9¹¹

13¹¹

Facilitatory mutations in the NADH dehydrogenase gene (ndh)⁶⁹, mutations of the promoter region of a key fatty acid synthesis gene (inhA)^70,71,72, and inhibitory mutations of a monooxygenase necessary for ethionamide activation (ethA)⁷²

Streptomycin

2nd

Antibiotic¹¹

1.0^20,21,60

25⁷³

7⁷³

Mutations to genes that dictate the shape of ribosomal protein S12 (rspL) or 16 s ribosomal RNA (rrs)^74,75,76 as well as inhibitory mutations of a 16S ribosomal RNA methyl transferase (gidB)^77,78

Amikacin

2nd

Semi-synthetic Antibiotic⁷⁹

0.5–2.2^20,21,80

17^79,81

17^79,81

Mutations to the genes that dictate the shape of 16S ribosomal RNA (rrs)^82,83,84 and loss of function mutations on the gene for a ribosome methyltransferase (tlyA)⁸⁵

Kanamycin A

2nd

Antibiotic¹¹

1.0–5.0 ^21,60,65,86

8⁸⁷

5⁸⁷

Mutations to the genes that dictate the shape of 16S ribosomal RNA (rrs)^82,83,84 and mutations in the promoter region of the gene for an N-acetyltransferase that plays a role in cell survival (eis)^88,89

Capreomycin IA/IB

2nd

Antibiotic¹¹

1.0–7.0^20,21,90

14⁹¹

7⁹¹

Mutations to the genes that dictate the shape of 16S ribosomal RNA (rrs)^84,85 and loss of function mutations on the gene for a ribosome methyltransferase (tlyA)^92,93

Para-amino salicylic acid

2nd

Chemo-therapeutic¹¹

0.45–2.0 ^20,60,94,95

1¹¹

3

Loss of function mutations in the gene for a thymidylate synthase critical to thymine biosynthesis and the folate pathway (thyA)^96,97,98

Levofloxacin

2nd

Chemo-therapeutic⁹⁹

0.5^20,100,101

8^99,102

8⁹⁹

Mutations in the DNA gyrase subunit A gene that reduces levofloxacin binding affinity (gyrA)^103,104