Sulfonamides: Sulfonamides form the core of the sulfa drugs, the first synthetic antibiotics discovered. They were discovered by Domagk as related arylazosulfonamides which were prepared as dyes but found to cure bacterial infections when given to people. Subsequent work showed that the azo compound found by Domagk underwent reductive cleavage to the active aminobenzenesulfonamide; the aminobenzenesulfonamide acts as a mimic of p-aminobenzoic acid, which inhibits dihydropteroate synthetase, an enzyme necessary for folate synthesis (Figure ) and thus for growth and metabolism. While bacteria can synthesize folates, mammals must obtain them through their diet; thus, bacteria are susceptible to folate inhibition but not mammals. Sulfa drugs are bacteriostatic against both Gram-negative and Gram-positive bacteria but are not bactericidal. Seven sulfa drugs have been approved by the US FDA as antibiotics -sulfanilamide (1937, R = H), sulfadiazine (1941, R = 2-pyrimidinyl), sulfapyridine (1942, R = 2-pyridinyl), sulfasalazine (1950 -an azo prodrug of sulfapyridine), sulfamethizole (1953, R = 5-methyl-1,3,4-thiadiazol-2-yl), sulfacetamide (1970, R = MeCO), and sulfamethoxazole (1982, R = 5-methyl-3-isoxazolyl) (Supplementary Table ). Bacteria have multiple resistance mechanisms for sulfonamides. Modification of dihydropteroate synthetase to prevent the binding of sulfonamides with substituents at the sulfonamide nitrogen in combination with other mutations to improve the activity of the mutant enzyme can restore growth to sulfonamide-inhibited bacteria. Alternatively, acylation or hydroxylation of the aniline nitrogen of sulfonamides abrogates binding to dihydropteroate synthetase. Beta-lactams: First reported by Alexander Fleming in 1929 , β-lactams are one of the most commonly prescribed drug classes. Penicillin G, the "wonder drug" produced by the Penicillium fungus, is the oldest member of this family, clinically used in the 1930s and playing a very important role in saving lives during WWII. These drugs have an essential structural feature, a highly reactive four-membered amide ring known as a "β-lactam" or "azetidinone". The antibacterial properties of β-lactams come from their inhibition of bacterial transpeptidases that catalyze the cross-linkage of peptidoglycan, a main component in bacterial cell wall synthesis. These transpeptidases, known as penicillin-binding proteins (PBPs), irreversibly and covalently bind to β-lactams via the nucleophilic attack of the serine residue in the PBPs active site to the lactam carbonyl which results in a stable acyl-enzyme complex. The structure, geometry, and stereochemical characteristics of β-lactams play a key role in this inhibition, for it mimics the enzyme-substrate, D-Ala-D-Ala dipeptide in peptidoglycans of the bacterial cell wall. Grampositive bacteria are more susceptible to β-lactams than gram-negative bacteria; mostly due to the higher concentration of peptidoglycan in the cell wall. This broad family of antibiotics can be divided into the structural classes shown in Supplementary Table .