A Quantitative Survey of Bacterial Persistence in the Presence of Antibiotics: Towards Antipersister Antimicrobial Discovery

Abstract

Background: Bacterial persistence to antibiotics relates to the phenotypic ability to survive lethal concentrations of otherwise bactericidal antibiotics. The quantitative nature of the time–kill assay, which is the sector’s standard for the study of antibiotic bacterial persistence, is an invaluable asset for global, unbiased, and cross-species analyses. Methods: We compiled the results of antibiotic persistence from antibiotic-sensitive bacteria during planktonic growth. The data were extracted from a sample of 187 publications over the last 50 years. The antibiotics used in this compilation were also compared in terms of structural similarity to fluorescent molecules known to accumulate in Escherichia coli. Results: We reviewed in detail data from 54 antibiotics and 36 bacterial species. Persistence varies widely as a function of the type of antibiotic (membrane-active antibiotics admit the fewest), the nature of the growth phase and medium (persistence is less common in exponential phase and rich media), and the Gram staining of the target organism (persistence is more common in Gram positives). Some antibiotics bear strong structural similarity to fluorophores known to be taken up by E. coli, potentially allowing competitive assays. Some antibiotics also, paradoxically, seem to allow more persisters at higher antibiotic concentrations. Conclusions: We consolidated an actionable knowledge base to support a rational development of antipersister antimicrobials. Persistence is seen as a step on the pathway to antimicrobial resistance, and we found no organisms that failed to exhibit it. Novel antibiotics need to have antipersister activity. Discovery strategies should include persister-specific approaches that could find antibiotics that preferably target the membrane structure and permeability of slow-growing cells.

Structural Similarities between Some Common Fluorophores Used in Biology, Marketed Drugs, Endogenous Metabolites, and Natural Products

“…Of course, some marketed pharmaceutical drugs that are transported into cells are, in fact, naturally fluorescent, including molecules such as anthracyclines [ 56 , 57 , 58 ], mepacrine (atebrin, quinacrine) [ 59 ], obatoclax [ 60 , 61 ], tetracycline derivatives [ 57 , 62 ] and topotecan [ 63 ], The same is true of certain vitamins such as riboflavin [ 64 , 65 ] (that necessarily have transporters, as cells cannot synthesise them), as well as certain bioactive natural products (e.g., [ 66 , 67 , 68 ]). As per this Special Issue, and in an era of increasing antimicrobial resistance [ 69 , 70 , 71 , 72 ], this is very much the case for novel antimicrobials, which classically come from natural products (e.g., [ 73 , 74 , 75 , 76 , 77 , 78 ]). If so, they might then serve as surrogate transporter substrates for them.…”

Deep learning and generative methods in cheminformatics and chemical biology: navigating small molecule space intelligently

“…Antimicrobial resistance is a well-known and major problem, and it would be desirable to find new antiinfectives (e.g. [140][141][142]). Thus, Collins and colleagues [143] trained a deep neural network on 2335 molecules that had been shown experimentally to inhibit the growth of E. coli.…”

The Transporter-Mediated Cellular Uptake and Efflux of Pharmaceutical Drugs and Biotechnology Products: How and Why Phospholipid Bilayer Transport Is Negligible in Real Biomembranes

“…In recent work [ 261 , 262 , 263 ], we have recognised that the existence of genome-wide knockout (and overexpression) collections allows for the high-throughput assessment of the uptake of small molecule substrates. Since fluorophores are perfectly good surrogates for these purposes [ 264 ], and their uptake admits easy assessment using flow cytometry [ 265 , 266 , 267 , 268 , 269 , 270 , 271 , 272 ], we have been able to assess the influence of the expression of individual transporters on the uptake of various fluorophores.…”