Table 1. The mutated residue positions most important for TEM extended-spectrum antibiotic resistance, according to measures from network theory (centrality rankings).
| Residue Number* | Count within Data- base | Node Degree Rank | Node Between-ness Rank | Described Function | References |
| 104 | 48 | 1 | 1 | The long K chain of E104K mutants interacts directly with carboxylic acid group of the substrate. | [9], [73] |
| 164 | 48 | 2 | 2 | Forms two salt bridges, to E171 and D179, critical for correct positioning of E166. The smaller mutant chain collapses the Ω-loop, resulting in an active site with greater accessibility. | [9], [74] |
| 238 | 38 | 3 | 3 | Expands the active site either by repositioning the B3 β-strand or by tilting the Ω-loop | [73], [75] |
| 240 | 31 | 4 | 4 | Interacts with substrate; possibly stabilizing. | [73], [76] |
| 182 | 27 | 5 | 5 | Increases the thermodynamic stability of the protein; could suppress misfolding and aggregation caused by other mutations. Acts as a global suppressor. | [9], [43], [77] |
| 265 | 20 | 7 | 9 | Unknown mechanism. Possibly important for enzyme stability. | [9] |
| 237 | 9 | 6 | 8 | Introduces another H-bond with carbonyl group of β-lactam ring. | [9], [73] |
| 173 | 5 | 9 | 6 | Increased resistance, specific for subset of cephalosporins. | [9] |
| 120 | 3 | 17 | 8 | Unknown mechanism. Possibly important for enzyme stability. | [25], [50], [51] |
| 254 | 3 | 8 | N/A | Unknown mechanism. Possibly stabilizing. | [9], [25] |
| 51 | 2 | 15 | 7 | Unknown mechanism. Possibly important for both enzyme activity and stability. | [9], [35] |
| 268 | 2 | 10 | 8 | Unknown mechanism. Possibly stabilizing. | [9] |
Degree centrality rank is based on how well connected a node is to its neighbors and how many neighbors it has (Methods). We interpret betweenness centrality as a representation of the information flow through a node from the entire community (Methods).
*Based on Ambler TEM β-lactamase numbering scheme [65]. Mutated residues that are highly ranked by the network centrality metrics have known functional impact previously described in the literature. While many of the mutations known to contribute to extended-spectrum resistance are highly frequent, the network also ranks highly the less frequent mutations with known contributions.