Discovery of Marine Natural Products as Promising Antibiotics against Pseudomonas aeruginosa

Abstract

Pseudomonas aeruginosa, one of the most intractable Gram-negative bacteria, has become a public health threat due to its outer polysaccharide layer, efflux transporter system, and high level of biofilm formation, all of which contribute to multi-drug resistance. Even though it is a pathogen of the highest concern, the status of the antibiotic development pipeline is unsatisfactory. In this review, we summarize marine natural products (MNPs) isolated from marine plants, animals, and microorganisms which possess unique structures and promising antibiotic activities against P. aeruginosa. In the last decade, nearly 80 such MNPs, ranging from polyketides to alkaloids, peptides, and terpenoids, have been discovered. Representative compounds exhibited impressive in vitro anti-P. aeruginosa activities with MIC values in the single-digit nanomolar range and in vivo efficacy in infectious mouse models. For some of the compounds, the preliminary structure-activity-relationship (SAR) and anti-bacterial mechanisms of selected compounds were introduced. Compounds that can disrupt biofilm formation or membrane integrity displayed potent inhibition of multi-resistant clinical P. aeruginosa isolates and could be considered as lead compounds for future development. Challenges on how to translate hits into useful candidates for clinical development are also proposed and discussed.

Isolation, whole-genome sequencing, and annotation of two antibiotic-producing and antibiotic-resistant bacteria, Pantoea rodasii RIT 836 and Pseudomonas endophytica RIT 838, collected from the environment

“…Carotenoids are organic, lipophilic, naturally-occurring terpenoid compounds that can range in color: yellow, orange, or red (410–510 nm) [ 52 ], which might explain the yellow-orange color of this bacterium’s colonies observed on agar plates and contribute to the antibiotic activity showed by RIT 836 in our inhibitory assays. Terpenes have the potential to inhibit microbes through molecular mechanisms involved in anti-quorum sensing, membrane disruption, and protein synthesis inhibition [ 53 , 54 ]. Carotenoids extracted from strains of Rhodotorula glutinis have been found to have antioxidant and antibacterial effects as a natural preservative [ 51 ].…”

Antifouling Potential of Ethyl Acetate Extract of Marine Bacteria Pseudomonas aeruginosa Strain RLimb

“…According to the study by Ahmadi et al [ 70 ], 74.41% of P. aeruginosa in their study were resistant to vancomycin. P. aeruginosa shares characteristics with other Gram-negative pathogens, such as an outer polysaccharide layer, multi-drug efflux transportees, and a high level of biofilm formation, which collectively increase the probability of resistance toward antibiotics [ 71 ].…”

β-Lactams from the Ocean

“…Moreover, as is seen with respect to the antimicrobial evaluation of terrestrial secondary metabolites, the antimicrobial evaluation of marine secondary metabolites likewise identifies innumerable structures possessing modest to good antibacterial activity [ 34 ]. Inventories of these structures are published regularly [ 15 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ]. Within these inventories are found structures that are truly distinctive, often in the multiple aspects of their biosynthesis, ring construction, and biological activity.…”