Searching for new antibacterial drugs among microbial species

TThe old adage “the enemy of my enemy is my friend” predates the discovery of antibiotics, and modern scientists recently found a way to put this adage into practice by discovering that peptides made by lung-colonizing bacteria act on other bacteria.

Their target is Streptococcus pneumoniaeAlso known as Streptococcus pneumoniae, this bacterium can cause pneumonia, meningitis and sepsis, especially in children, the elderly and those with weakened immune systems.¹ In a recently published study, Communication Biologyled by a team Lucy HathawayA microbiologist from the University of Bern said that members of the resident respiratory system and occasional pathogens Klebsiella pneumoniae Released a peptide that specifically inhibits Streptococcus pneumoniaeGrowth.²

Antibiotic resistance On the riseResearchers are searching for new treatments. Streptococcus pneumoniaeespecially, They are good at becoming resistant to therapeutic drugs.³ “The bacterium has a natural ability to recombine, so it can pick up DNA not only from other pneumococci but also from closely related bacterial species that live in the nasopharynx,” Hathaway says. This DNA uptake can change the proteins and carbohydrates that the pneumococci express on their surface, potentially leading to antibiotic resistance.

Hathaway studies the interactions between pneumococci and other bacterial species. Before pneumococci can infect humans, they must colonize the nasopharynx and compete for a place in the bacterial community. Resident bacteria It is usually there.^Four Streptococcus pneumoniae Bacteria can absorb oligopeptides secreted by surrounding microbes, which then affect the bacterial transcriptome and proteome. Hathaway’s team previously reported Streptococcus pneumoniae The transporter, named Ami-AliA/AliB permease, peptide release Klebsiella pneumoniae These peptides were found to inhibit the growth of pneumococci.^Five

In a recent study, researchers Klebsiella pneumoniae The secretome was analyzed by liquid chromatography-tandem mass spectrometry and further peptides were identified. Streptococcus pneumoniae “The peptide inhibited bacterial growth. They named the interspecies peptide V11A, after its length of 11 amino acids. Scientists may one day be able to use this and similar peptides as anti-inflammatory drugs.” Streptococcus pneumoniae.

“The most interesting result is that V11A inhibits the growth of pneumococci not only in peptide-free medium but also in human cerebrospinal fluid,” Hathaway says. “In patients with meningitis, pneumococci [cerebrospinal fluid]So if we have tools to curb that growth, I think that’s potentially very useful.”

The researchers found that V11A Streptococcus pneumoniae It relied on the presence of a functional Ami-AliA/AliB permease to attack strains, including clinical isolates and antibiotic-resistant strains. Indeed, strains that resisted V11A attack carried known mutations in parts of the permease complex. The growth effect was bacteriostatic rather than bactericidal, meaning the peptide inhibited bacterial growth without killing the cells. “This is potentially advantageous for anti-pneumococcal therapy, because pneumococci produce a lytic toxin, pneumolysin, which binds to cholesterol in eukaryotic cell membranes and causes inflammatory cell damage,” he said. Daniel NealThe University of Dundee microbiologist was not involved in the study. [is] Being able to block the growth of pneumococci rather than lysing the bacteria directly could be a real advantage.”

Hathaway and his colleagues next investigated the effect of V11A on competence – the ability of bacteria to take up extracellular DNA during transformation. Streptococcus pneumoniaeThe characteristic chain-like morphology of the growing cells makes them look like strings of beads. Some antibiotics Triggering abilities elongated bacterial chains, whereas V11A treatment had the opposite effect, decreasing conversion rate and chain length.⁶ The researchers found that the longer the chain, the Attachment to epithelial cellsHathaway investigated whether the V11A could produce the opposite effect. ⁷ After confirming that the peptides were not toxic in vitro or in vivo, the researchers demonstrated that the peptides inhibited pneumococcus adhesion to airway cell cultures, Streptococcus pneumoniae Prevents colonization of the rat nasopharynx.

To better understand the phenotypic changes brought about by V11A, the researchers sequenced pneumococci exposed to the peptide and found multiple changes in gene expression, many of which were Streptococcus pneumoniae Analysis of the proteome revealed that genes involved in adhesion, competence, and fatty acid and amino acid biosynthesis were up- or down-regulated, consistent with the effects of V11A on transformation and colonization. Neal said that the effect on competence could be a particularly beneficial feature for antipneumococcal drugs, given the bacteria’s propensity to absorb DNA. “If we can limit the amount of exogenous DNA taken up by the pneumococcus, then in theory we should be able to slow the emergence and spread of resistance,” he added.

Not only was V11A able to overwhelm antibiotic-resistant bacteria in a non-lytic manner and reduce transformation and adherence, but the peptide’s species specificity is further evidence that it may be a promising anti-pneumococcal therapeutic, says Hathaway: V11A had no effect on other common bacteria that colonize the lungs. Influenza Haemophilus influenzae or Staphylococcus aureusImportant details when developing narrow spectrum drugs. “By administering peptides to the microbiome, for example in the respiratory system, you’re targeting pathogens without interfering with harmless or beneficial bacteria,” Hathaway says.

Having discovered that V11A enters pneumococci via a permease, the researchers next wanted to understand how this peptide affects gene expression after entry.. Additionally, Hathaway’s team plans to optimize the dosage and method of administration, conduct further toxicity studies, and examine whether resistance to V11A’s as yet unknown mechanisms develops over time. “We’re really excited to see if we can use this peptide to inhibit the disease,” Hathaway said.