Antimicrobial peptides (AMPs) are distributed across all kingdoms of life and are an indispensable component of host defenses. They consist of predominantly short cationic peptides with a wide variety of structures and targets. Given the ever-emerging resistance of various pathogens to existing antimicrobial therapies, AMPs have recently attracted extensive interest as potential therapeutic agents. As the discovery of new AMPs has increased, many databases specializing in AMPs have been developed to collect both fundamental and pharmacological information. In this review, we summarize the sources, structures, modes of action, and classifications of AMPs. Additionally, we examine current AMP databases, compare valuable computational tools used to predict antimicrobial activity and mechanisms of action, and highlight new machine learning approaches that can be employed to improve AMP activity to combat global antimicrobial resistance.

The use of fosfomycin for treatment of systemic infections due to MDR Pseudomonas aeruginosa is increasing. However, pharmacodynamic data for fosfomycin are limited. Sixty-four clinical isolates of P. aeruginosa (MDR and non-MDR) from two Australian hospitals were collected; 59 isolates were from patients with cystic fibrosis and 5 isolates were from critically ill patients. The in vitro pharmacodynamic properties of fosfomycin (disodium) were investigated via MICs (all isolates) and, for selected isolates, via time–kill kinetics (static and dynamic models; concentration range, 1–1024 mg/L), population analysis profiles (PAPs) and post-antibiotic effect (PAE). Two inocula (∼10⁶ and ∼10⁸ cfu/mL) were included in static time–kill studies to examine the effect of inocula on bacterial killing. MICs ranged from 1 to >512 mg/L, with 61% of isolates considered fosfomycin susceptible (MIC ≤64 mg/L). The MIC distributions for MDR and non-MDR isolates were similar. Baseline PAPs indicated heteroresistance in all isolates tested. Time–kill studies showed moderate (maximum killing ∼3 log₁₀ cfu/mL), time-dependent killing at the low inoculum with regrowth at 24 h. Most concentrations resulted in complete replacement of fosfomycin-susceptible colonies by fosfomycin-resistant colonies. Bacterial killing was virtually eliminated at the high inoculum. The PAE ranged from 0.3 to 5.5 h. These data suggest monotherapy with fosfomycin may be problematic for the treatment of infections caused by P. aeruginosa. Further investigation of fosfomycin combination therapy is warranted.

Fosfomycin resistance occurs rapidly with monotherapy. This study systematically investigated bacterial killing and emergence of fosfomycin resistance with fosfomycin combinations against Pseudomonas aeruginosa. Four clinical isolates and a reference strain of P. aeruginosa were employed. Combinations of fosfomycin plus polymyxin B, tobramycin or ciprofloxacin were examined over 24 h using time–kill studies (inocula ∼10⁶ cfu/mL) incorporating clinically relevant concentrations (fosfomycin, 30, 150 or 300 mg/L; polymyxin B, 0.5, 1 or 2 mg/L; tobramycin, 0.5, 1.5 or 4 mg/L; ciprofloxacin, 0.5, 1 or 2.5 mg/L). Microbiological response was examined by log changes and population analysis profiles. Against susceptible isolates, monotherapy produced varying degrees of initial killing followed by rapid regrowth. Fosfomycin plus polymyxin B or tobramycin produced greater initial killing (up to ∼4 log₁₀ cfu/mL) with many concentrations compared with monotherapy against fosfomycin-susceptible (FOF^S) isolates. With these combinations, synergy or additivity was observed in 54 (67%) and 49 (60%) of 81 cases (nine combinations across three isolates at three timepoints) for polymyxin B and tobramycin, respectively. Substantial improvements in killing were absent against fosfomycin-resistant (FOF^R) isolates. For fosfomycin/ciprofloxacin combinations, synergy or additivity was observed against FOF^R isolates in 33 of 54 (61%) cases (nine combinations across two isolates at three timepoints), while improvements in killing were largely absent against FOF^S isolates. No combination prevented emergence of fosfomycin resistance. Against P. aeruginosa, fosfomycin in combination with polymyxin B or tobramycin (FOF^S isolates) or ciprofloxacin (FOF^R isolates) increased bacterial killing, but did not suppress emergence of fosfomycin resistance.