Table 1.

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

Drug name	1st or 2nd Line17	Antibiotic/ Chemo-therapeutic	MIC for Mtb (µg/mL)	# of Steps for synthesis	# of Precursors*	Mechanism of resistance
Isoniazid	1st	Chemo-therapeutic11	0.02–0.218–21	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: 0.05–0.538–21,26–46 Rifapentine: 0.015–0.6 20,21,21,45	2747	747,48	Rifampicin: Mutations that change the binding affinity of the b subunit of bacterial RNA polymerase for rifampicin (rpoB)49–51 Rifapentine: Mutations of rpoB, often the same as those that confer rifampicin resistance49,51
Pyrazinamide	1st	Chemo-therapeutic11	12.5–2020,52,53	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 pyrazinamide54,57
Ethambutol	1st	Chemo-therapeutic11	0.5–2.0 19–21,58–60	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	10–5021,60,65	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)70–72, and inhibitory mutations of a monooxygenase necessary for ethionamide activation (ethA)72
Streptomycin	2nd	Antibiotic11	1.020,21,60	2573	773	Mutations to genes that dictate the shape of ribosomal protein S12 (rspL) or 16 s ribosomal RNA (rrs)74–76 as well as inhibitory mutations of a 16S ribosomal RNA methyl transferase (gidB)77,78
Amikacin	2nd	Semi-synthetic Antibiotic79	0.5–2.220,21,80	1779,81	1779,81	Mutations to the genes that dictate the shape of 16S ribosomal RNA (rrs)82–84 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)82–84 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	1.0–7.020,21,90	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)96–98
Levofloxacin	2nd	Chemo-therapeutic99	0.520,100,101	899,102	899	Mutations in the DNA gyrase subunit A gene that reduces levofloxacin binding affinity (gyrA)103,104

Pathways with biologically available precursors in bold.

* Commonly available small molecules, such as, H₂, O₂, and H₂O were not counted as antibiotic precursors. Common cofactors such as NAD⁺, ATP, FAD, and acetyl CoA were also not listed as antibiotic precursors.

^† Rifamycin SV has several derivatives. These include, notably, Rifampicin, Rifapentine, and Rifabutin¹⁰⁵.