We hypothesized that small heterocyclic or nitrogen-containing compounds could act as RND efflux pump inhibitors (EPIs). To ascertain possible EPIs, we sought to identify compounds that synergized with substrates of RND efflux pumps for wild-type bacteria and those that overexpress an efflux pump, but had no synergistic activity against strains in which a gene encoding a component of the AcrAB-TolC efflux pump had been inactivated. Twenty-six compounds plus l-phenylalanyl-l-arginyl-β-naphthylamide (PAβN) and carbonyl cyanide m-chlorophenylhydrazone (CCCP) were screened by bioassay to identify compounds that synergized with ciprofloxacin for a range of Enterobacteriaceae and Pseudomonas aeruginosa. The MICs of ciprofloxacin, tetracycline, chloramphenicol, erythromycin and ethidium bromide ± synergizing compounds were determined, and the ability to inhibit the efflux of Hoechst 33342 was measured. Two compounds, trimethoprim and epinephrine, consistently showed synergy with antibiotics for most strains. The combinations did not show synergy for Salmonella enterica serovar Typhimurium in which the AcrAB-TolC efflux pump was inactive. Both compounds inhibited the efflux of Hoechst 33342. Two compounds, trimethoprim and epinephrine, which are already licensed for use in man, may warrant further analysis as EPIs. The combination of trimethoprim with another antibiotic is a well-used combination in anti-infective chemotherapy, and so combination with another agent, such as a quinolone, may be a viable option and further studies are now required.

Antimicrobial resistance has been posing an alarming threat to the treatment of infectious diseases over the years. Ineffectiveness of the currently available synthetic and semisynthetic antibiotics has led the researchers to discover new molecules with potent antimicrobial activities. To overcome the emerging antimicrobial resistance, new antimicrobial compounds from natural sources might be appropriate. Secondary metabolites from natural sources could be prospective candidates in the development of new antimicrobial agents with high efficacy and less side effects. Among the natural secondary metabolites, diterpenoids are of crucial importance because of their broad spectrum of antimicrobial activity, which has put it in the center of research interest in recent years. The present work is aimed at reviewing recent literature regarding different classes of natural diterpenes and diterpenoids with significant antibacterial, antifungal, antiviral, and antiprotozoal activities along with their reported structure–activity relationships. This review has been carried out with a focus on relevant literature published in the last 5 years following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 229 diterpenoids from various sources like plants, marine species, and fungi are summarized in this systematic review, including their chemical structures, classification, and significant antimicrobial activities together with their reported mechanism of action and structure–activity relationships. The outcomes herein would provide researchers with new insights to find new credible leads and to work on their synthetic and semisynthetic derivatives to develop new antimicrobial agents.