Better living through chemistry: Addressing emerging antibiotic resistance

Abstract

The increasing emergence of multidrug-resistant bacteria is recognized as a major threat to human health worldwide. While the use of small molecule antibiotics has enabled many modern medical advances, it has also facilitated the development of resistant organisms. This minireview provides an overview of current small molecule drugs approved by the US Food and Drug Administration (FDA) for use in humans, the unintended consequences of antibiotic use, and the mechanisms that underlie the development of drug resistance. Promising new approaches and strategies to counter antibiotic-resistant bacteria with small molecules are highlighted. However, continued public investment in this area is critical to maintain an edge in our evolutionary "arms race" against antibiotic-resistant microorganisms. Impact statement The alarming increase in antibiotic-resistant microorganisms is a rapidly emerging threat to human health throughout the world. Historically, small molecule drugs have played a major role in controlling bacterial infections and they continue to offer tremendous potential in countering resistant organisms. This minireview provides a broad overview of the relevant issues, including the diversity of FDA-approved small molecule drugs and mechanisms of drug resistance, unintended consequences of antibiotic use, the current state of development for small molecule antibacterials and financial challenges that impact progress towards novel therapies. The content will be informative to diverse stakeholders, including clinicians, basic scientists, translational scientists and policy makers, and may be used as a bridge between these key players to advance the development of much-needed therapeutics.

Keywords: Bacteria; drugs; mechanisms; pharmacology; resistance; small molecule inhibitors.

Figure 1.

Anatomy of Gram-negative and Gram-positive bacteria and their susceptibility to antibiotics. (a) The cell wall of Gram-negative bacteria includes outer and inner (cytoplasmic) membranes, which form the barriers of the periplasmic space that contains a thin layer of peptidoglycan. The outer leaflet of the outer membrane contains lipopolysaccharide (LPS) consisting of lipid A and O-polysaccharide. The outer membrane contains porins, which provide entrance to the periplasm for some molecules. (b) The outer wall of Gram-positive bacteria contains a thick layer of peptidoglycan that retains the crystal violet stain used in the Gram stain test. Teichoic acids, which are not found in Gram-negative bacteria, are called lipoteichoic acids (LTA) when anchored to the cytoplasmic membrane. Gram-positive bacteria lack an outer membrane and thus are more susceptible to antibiotics. Both Gram-negative and Gram-positive cell walls contain efflux pumps and other active pumps that can export intracellular molecules, including antibiotics. (c) Gram-negative bacteria are intrinsically resistant to many antibiotics due to the architecture of their cell walls. Nevertheless, a variety of antibiotics are effective by targeting the synthesis of protein, the cell wall or nucleic acids. Resistance to antibiotics can be mediated by increased efflux by pumps and reduced permeability through porins in addition to other mechanisms, including target mutation, overexpression or protection and drug inactivation.

Figure 2.

Small molecule antibacterial drugs approved by the US Food and Drug Administration (FDA) for use in humans. This plot shows the number of drugs approved within five-year periods from 1939 until 2017 (all drugs are listed in Table 1). The 157 drugs are grouped according to 20 classifications as shown by the legend. The greatest number of drugs were approved between 1981 and 1985, consisting of 19 antibacterials that span more than six classifications. During the past three decades, the number of approved small molecule antibacterial drugs has steadily decreased.

Figure 3.

Chemical space-time of β-lactam antibacterial drugs. The dots indicate structures of β-lactam antibacterial drugs in a 2-dimensional chemical space. The distance between dots reflects the extent of structural similarity, with similar structures in closer proximity. The color and size of the dots corresponds to the year of FDA-approval, with more recent approvals indicated by a color closer to the blue end of the spectrum and a smaller size. The maximal common substructure (MSC) clustering was performed with a similarity threshold of 0.60 using the StarDrop scientific software suite (version: 6.2.0, Optibrum Ltd, Cambridge, UK). The clustering resulted in 11 MCS clusters and eight singletons (Table 1). In oder to characterize the diversity among β-lactam structures, they were embedded in a 2-dimensional space using the t-distributed stochastic neighbor embedding algorithm of StarDrop.^,