The use of and search for drugs and dietary supplements derived from plants have accelerated in recent years. Ethnopharmacologists, botanists, microbiologists, and natural-products chemists are combing the Earth for phytochemicals and “leads” which could be developed for treatment of infectious diseases. While 25 to 50% of current pharmaceuticals are derived from plants, none are used as antimicrobials. Traditional healers have long used plants to prevent or cure infectious conditions; Western medicine is trying to duplicate their successes. Plants are rich in a wide variety of secondary metabolites, such as tannins, terpenoids, alkaloids, and flavonoids, which have been found in vitro to have antimicrobial properties. This review attempts to summarize the current status of botanical screening efforts, as well as in vivo studies of their effectiveness and toxicity. The structure and antimicrobial properties of phytochemicals are also addressed. Since many of these compounds are currently available as unregulated botanical preparations and their use by the public is increasing rapidly, clinicians need to consider the consequences of patients self-medicating with these preparations.

Plant Products as Antimicrobial Agents

Biofilms--matrix-enclosed microbial accretions that adhere to biological or non-biological surfaces--represent a significant and incompletely understood mode of growth for bacteria. Biofilm formation appears early in the fossil record (approximately 3.25 billion years ago) and is common throughout a diverse range of organisms in both the Archaea and Bacteria lineages, including the 'living fossils' in the most deeply dividing branches of the phylogenetic tree. It is evident that biofilm formation is an ancient and integral component of the prokaryotic life cycle, and is a key factor for survival in diverse environments. Recent advances show that biofilms are structurally complex, dynamic systems with attributes of both primordial multicellular organisms and multifaceted ecosystems. Biofilm formation represents a protected mode of growth that allows cells to survive in hostile environments and also disperse to colonize new niches. The implications of these survival and propagative mechanisms in the context of both the natural environment and infectious diseases are discussed in this review.

/pdf/bacterial-biofilms-from-the-natural-environment-to-4pdlw3zbzj.pdf

Bacterial biofilms: from the natural environment to infectious diseases.

https://pubs.rsc.org/en/content/articlepdf/2019/NP/C8NP00092A

Marine natural products.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(01)05321-1.pdf

Antibiotic resistance of bacteria in biofilms

https://www.cell.com/trends/microbiology/pdf/S0966-842X(00)01913-2.pdf

Mechanisms of biofilm resistance to antimicrobial agents

Antibiotic resistance is spreading faster than the introduction of new compounds into clinical practice, causing a public health crisis. Most antibiotics were produced by screening soil microorganisms, but this limited resource of cultivable bacteria was overmined by the 1960s. Synthetic approaches to produce antibiotics have been unable to replace this platform. Uncultured bacteria make up approximately 99% of all species in external environments, and are an untapped source of new antibiotics. We developed several methods to grow uncultured organisms by cultivation in situ or by using specific growth factors. Here we report a new antibiotic that we term teixobactin, discovered in a screen of uncultured bacteria. Teixobactin inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid). We did not obtain any mutants of Staphylococcus aureus or Mycobacterium tuberculosis resistant to teixobactin. The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance.

https://courses.washington.edu/medch582/PDFs/2015_Feb9_David.pdf

A new antibiotic kills pathogens without detectable resistance

A biofilm is a population of cells growing on a surface and enclosed in an exopolysaccharide matrix. Biofilms are notoriously difficult to eradicate and are a source of many recalcitrant infections. The nature of bacterial biofilm resistance to antimicrobials is the subject of the present minireview. Pathogenic yeast such as Candida albicans also form recalcitrant biofilms, and this topic has recently been reviewed (5). Resistance is an ability of a microorganism to grow in the presence of an elevated level of an antimicrobial. In short, a strain for which the MIC is increased is resistant. By this conventional criterion, biofilm cells do not necessarily show increased resistance. With some exceptions, biofilm cells do not grow better than planktonic cells in the presence of a broad range of antimicrobials. This is evident from examination of susceptibility data in the biofilm literature (33). However, in most biofilm susceptibility studies, only survival of cells in a preformed biofilm rather than the ability of a biofilm to grow is recorded. Accordingly, the reported “resistance” describes an increased resistance of cells to killing. This is indeed what biofilms are good at: they are not easily eradicated by cidal antimicrobials. The ability of antimicrobials to inhibit biofilm growth indicates that they are able to diffuse through the biofilm and act normally against their targets. Why, then, do biofilm cells not die? This is the crux of the problem and the riddle that needs to be solved.

https://journals.asm.org/doi/pdf/10.1128/AAC.45.4.999-1007.2001

Riddle of Biofilm Resistance

Several well-recognized puzzles in microbiology have remained unsolved for decades. These include latent bacterial infections, unculturable microorganisms, persister cells and biofilm multidrug tolerance. Accumulating evidence suggests that these seemingly disparate phenomena result from the ability of bacteria to enter into a dormant (non-dividing) state. The molecular mechanisms that underlie the formation of dormant persister cells are now being unravelled and are the focus of this Review.

http://www.medicinabiomolecular.com.br/biblioteca/pdfs/Cancer/ca-3102.pdf

Persister cells, dormancy and infectious disease

The spread of resistant bacteria, leading to untreatable infections, is a major public health threat but the pace of antibiotic discovery to combat these pathogens has slowed down. Most antibiotics were originally isolated by screening soil-derived actinomycetes during the golden era of antibiotic discovery in the 1940s to 1960s. However, diminishing returns from this discovery platform led to its collapse, and efforts to create a new platform based on target-focused screening of large libraries of synthetic compounds failed, in part owing to the lack of penetration of such compounds through the bacterial envelope. This article considers strategies to re-establish viable platforms for antibiotic discovery. These include investigating untapped natural product sources such as uncultured bacteria, establishing rules of compound penetration to enable the development of synthetic antibiotics, developing species-specific antibiotics and identifying prodrugs that have the potential to eradicate dormant persisters, which are often responsible for hard-to-treat infections.

Platforms for antibiotic discovery

Poly(4-vinyl-N-alkylpyridinium bromide) was covalently attached to glass slides to create a surface that kills airborne bacteria on contact The antibacterial properties were assessed by spraying aqueous suspensions of bacterial cells on the surface, followed by air drying and counting the number of cells remaining viable (ie, capable of growing colonies) Amino glass slides were acylated with acryloyl chloride, copolymerized with 4-vinylpyridine, and N-alkylated with different alkyl bromides (from propyl to hexadecyl) The resultant surfaces, depending on the alkyl group, were able to kill up to 94 +/- 4% of Staphylococcus aureus cells sprayed on them A surface alternatively created by attaching poly(4-vinylpyridine) to a glass slide and alkylating it with hexyl bromide killed 94 +/- 3% of the deposited S aureus cells On surfaces modified with N-hexylated poly(4-vinylpyridine), the numbers of viable cells of another Gram-positive bacterium, Staphylococcus epidermidis, as well as of the Gram-negative bacteria Pseudomonas aeruginosa and Escherichia coli, dropped more than 100-fold compared with the original amino glass In contrast, the number of viable bacterial cells did not decline significantly after spraying on such common materials as ceramics, plastics, metals, and wood

https://www.pnas.org/content/pnas/98/11/5981.full.pdf

Kim Lewis

Papers

A new antibiotic kills pathogens without detectable resistance

Riddle of Biofilm Resistance

Persister cells, dormancy and infectious disease

Platforms for antibiotic discovery

Designing surfaces that kill bacteria on contact