Leveraging Marine Natural Products as a Platform to Tackle Bacterial Resistance and Persistence

Abstract

Conspectus Antimicrobial resistance to existing antibiotics represents one of the greatest threats to human health and is growing at an alarming rate. To further complicate treatment of bacterial infections, many chronic infections are the result of bacterial biofilms that are tolerant to treatment with antibiotics because of the presence of metabolically dormant persister cell populations. Together these threats are creating an increasing burden on the healthcare system, and a “preantibiotic” age is on the horizon if significant action is not taken by the scientific and medical communities. While the golden era of antibiotic discovery (1940s–1960s) produced most of the antibiotic classes in clinical use today, followed by several decades of limited development, there has been a resurgence in antibiotic drug discovery in recent years fueled by the academic and biotech sectors. Historically, great success has been achieved by developing next-generation variants of existing classes of antibiotics, but there remains a dire need for the identification of novel scaffolds and/or antimicrobial targets to drive future efforts to overcome resistance and tolerance. In this regard, there has been no more valuable source for the identification of antibiotics than natural products, with 69–77% of approved antibiotics either being such compounds or being derived from them. Our group has developed a program centered on the chemical synthesis and chemical microbiology of marine natural products with unusual structures and promising levels of activity against multidrug-resistant (MDR) bacterial pathogens. As we are motivated by preparing and studying the biological effects of these molecules, we are not initially pursuing a biological question but instead are allowing the observed phenotypes and activities to guide the ultimate project direction. In this Account, our recent efforts on the synoxazolidinone, lipoxazolidinone, and batzelladine natural products will be discussed and placed in the context of the field’s greatest challenges and opportunities. Specifically, the synoxazolidinone family of 4-oxazolidinone-containing natural products has led to the development of several chemical methods to prepare antimicrobial scaffolds and has revealed compounds with potent activity as adjuvants to treat bacterial biofilms. Bearing the same 4-oxazolidinone core, the lipoxazolidinones have proven to be potent single-agent antibiotics. Finally, our synthetic efforts toward the batzelladines revealed analogues with activity against a number of MDR pathogens, highlighted by non-natural stereochemical isomers with superior activity and simplified synthetic access. Taken together, these studies provide several distinct platforms for the development of novel therapeutics that can add to our arsenal of scaffolds for preclinical development and can provide insight into the biochemical processes and pathways that can be targeted by small molecules in the fight against antimicrobial-resistant and -tolerant infections. We hope that this work will s...

β-Lactams from the Ocean

“…Synthetic access to cyslabdan structures is, however, established [ 94 ]. Lipoxazolidinones are a class of marine-derived Gram-positive antibiotics [ 95 , 96 ]. They have several outstanding attributes: potent Gram-positive antibacterial activity (MRSA strains, MIC ≤2 mg·L −1 ), dual mechanisms of action (inhibition of both peptidoglycan and protein biosynthesis) with low frequency of resistance mutation, and accessibility to synthetic modification, with the possibility of expansion of their antibacterial activity to Gram-negative bacteria [ 97 ].…”

Strategies to Improve the Potency of Oxazolidinones towards Bacterial Biofilms

“…Synoxazolidinone A and its related natural product, synoxazolidinone C, [153] have been shown to exhibit anti‐fouling properties against a variety of marine bacteria [154] . Pierce and colleagues [139,155] identified 2‐dichloroalkyl‐5‐benzylidene‐4‐oxazolidinones (17) (Table 1) as modulators of MRSA biofilms (ATCC BAA 44). Through preparation of a series of analogues, key structural features were identified for anti‐biofilm potency (measured as biofilm inhibition using the established crystal violet staining protocol) [156] .…”

Exploration of Chemical Biology Approaches to Facilitate the Discovery and Development of Novel Antibiotics

“…Darobactin showed activity, both in vitro and in vivo, against Gram-negative pathogens; however, resistance was detected via mutations on its target protein, the b-barrel, outer membrane protein periplasmic chaperone (BamA) (13). Marine invertebrates have also been explored for antimicrobial natural products, and a variety of compounds from different chemical classes such as oxazolidinones and guanidinium alkaloids have been reported in recent literature (14).…”

“…Although no antibiotics discovered through HTS methods have made it to the clinics so far, recent improvements in the antibiotic discovery pipeline have resulted in promising new therapeutic leads (4). A combination of HTS with rational design Abbreviations: CuAAC, copper (I)-catalyzed azide-alkyne cycloaddition; MoA(s), mechanism(s) of action; HTS, high-throughput screening; FDA, Food and Drug Administration; BamA, component A of the b-barrel assembly machinery complex; DBO, diazabicyclooctane; SPRR, structure-porin permeation relationships; ESKAPE, Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species; JNK, c-Jun N-terminal kinase; NRP(s), non-ribosomal peptide(s); antiSMASH, antibiotics and secondary metabolite analysis shell; BGC(s), biosynthetic gene cluster(s) (BGC); NRPS(s), non-ribosomal peptide synthetase(s); NMR, nuclear magnetic resonance; IC 50 , half maximal inhibitory concentration; ABP(s), activity-based probe(s); ABPP, activity-based probe profiling; PG, peptidoglycans; LPS, lipopolysaccharides; CPS, capsular polysaccharides; VRSA, vancomycin-resistant S. aureus; VSSA, vancomycinsensitive S. aureus; SA, staphyloferrin A; BONCAT, bioorthogonal noncanonical amino acid tagging; DiZPK, ((3-(3-methyl-3H-diazirin-3-yl)propamino) carbonyl)-N ϵ -L -lysine; ACPK, N ϵ -((((1R,2R)-2-azidocyclopentyl)oxy)carbonyl)-holds great promise in producing new scaffolds to overcome resistance and expand pathogen scope given the advances in synthetic chemistry and an increased knowledge on the desired pharmacokinetic properties of antibiotics (3,14,15). Moreover, a switch from reductionist genes-to-drugs studies to more comprehensive systems-level approaches in antibacterial drug discovery has proven fundamental to identify antibiotics with novel MoAs and less prone to resistance (3).…”