The Chemical Relationship Among Beta-Lactam Antibiotics and Potential Impacts on Reactivity and Decomposition

Abstract

Beta-lactam antibiotics remain one of the most commonly prescribed drug classes, but they are limited by their propensity to cause hypersensitivity reactions (e.g., from allergy to anaphylaxis) as well as by the emergence of bacteria with a myriad of resistance mechanisms such as β-lactamases. While development efforts continue to focus on overcoming resistance, there are ongoing concerns regarding cross-contamination of β-lactams during manufacturing and compounding of these drugs. Additionally, there is a need to reduce levels of drugs such as β-lactam antibiotics in waste-water to mitigate the risk of environmental exposure. To help address future development of effective remediation chemistries and processes, it is desired to better understand the structural relationship among the most common β-lactams. This study includes the creation of a class-wide structural ordering of the entire β-lactam series, including both United States Food and Drug Association (US-FDA)-approved drugs and experimental therapies. The result is a structural relational map: the "Lactamome," which positions each substance according to architecture and chemical end-group. We utilized a novel method to compare the structural relationships of β-lactam antibiotics among the radial cladogram and describe the positioning with respect to efficacy, resistance to hydrolysis, reported hypersensitivity, and Woodward height. The resulting classification scheme may help with the development of broad-spectrum treatments that reduce the risk of occupational exposure and negative environmental impacts, assist practitioners with avoiding adverse patient reactions, and help direct future drug research.

Keywords: antibiotic allergy (including penicillin and cephalosporin β-lactams); antimicrobial activity; chemical informatics; deactivation; decomposition; hydrolysis; lactam antibiotics.

FIGURE 1

The chemical graphs and scaffold of primary examples of major β-lactam antibiotic classes. Common atom numbering scheme of the chemotype is depicted and oriented above the example β-lactam ring. The X may be a carbon, an oxygen atom, or a sulfur atom. For example, penem structures with X=C are “carbapenems”; penem structures with X=O are “oxapenems”; and penem structures with X=S are “thiapenems,” or more commonly, simply “penems.”

FIGURE 2

Structural basis of lactam activity. (A) The D-Ala-D-Ala amino acid is depicted in red. (B) The 1st generation penam ampicillin is depicted in black. (C) D-Ala-D-Ala dipeptide overlay with the β-lactam ampicillin antibiotic.

FIGURE 3

Structural flexibility of β-lactams and the h-Woodward coefficient. (A) General bicyclic β-lactam structure rendered to show pyramidal nitrogen. (B) Depiction of h-Woodward, defined by height of nitrogen to trigonal pyramid ligand base. (C) Faropenem depicted in stick form. (D) Faropenem energy minimized (using MOE with the Amber10:ETH forcefield) and angle of the bent nitrogen bonds showing the h-Woodward of 0.5 Å.

FIGURE 4

The Lactamome: Radial chemogram of major β-lactams by chemical similarity. Clustering used hierarchical complete linkage MAACS-keyed Tanimoto coefficient. Clustering was performed using ChemMine and visualized using Dendroscope (Huson et al., 2007; Backman et al., 2011). Colors indicate major chemotypes. Note that the oxacephems: moxalactam and flomoxef, are colored purple. Bolded lactams marked with an asterisk indicate drugs with high allergy potential (>10%) relating to the R₁ benzyl groups.

FIGURE 5

Lactamomes depicting (A) chemotype, (B) compound generation, and (C) h-Woodward values. (A) The chemotype is a reproduction of Figure 4 to aid comparisons to the other figures. (B) The generational lactamome assigns generation levels (1st–5th) to individual drugs based on how they most currently referenced in literature. Individual drugs that do not conform to generational naming are colored in black. (C) h-Woodward lactamome is colored using a heatmap with higher h-Woodward values in green and lower h-Woodward values in red. Bolded lactams marked with an asterisk indicate drugs with high allergy (>10%) relating to the R₁ benzyl groups.

FIGURE 6

Antimicrobial spectra of β-lactams. Clinical activity data were taken from The Stanford Guide to Antimicrobial Therapy. A fractional coverage index was calculated using a weighted average of categorical coverage values reported. Heatmap color range is from green indicating high coverage and red indicating low coverage. Beta-lactams are ordered from highest h-Woodward value (ertapenem) to lowest (aztreonam).

FIGURE 7

In vitro antimicrobial activity of lactams against S. pyogenes. A review of the literature on Gram-positive β-lactam activity was conducted in which susceptibility data were gleaned from 95 studies reporting data for at least 10 strains. MIC₅₀ (presented as log values) were amassed, and geometric mean and geometric standard deviation were calculated. Geometric means for entire classes (e.g., penems) are shown in gray. Beta-lactams are ordered from highest h-Woodward value (ertapenem) to lowest (aztreonam).

FIGURE 8

Structural representation of R₁ and R₂ chemical groups in cephem backbone.