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With the increasing development of antibiotic resistance among key bacterial pathogens, there is an urgent need to discover novel classes of antibiotics. Although antimicrobial peptides (AMP) with their specific mode of action are considered major candidates for next-generation antibiotics, several challenges limit the use of these peptides for therapeutic applications. In a large body of research, the focus is given to different approaches to the chemical modification of AMPs and how these modifications may improve the stability, antibiotic activity, proteolytic activity and prevent the cytotoxicity and side effects of AMPs. On the other hand, another group of research investigates the delivery of AMPs via nanocarrier systems as strategies used to enhance stability, control the release of peptides and reduce adverse peptide-related side effects, as well as improve their anti-microbial activities. In the present article, we surveyed most recently published researches that provide us with good knowledge on structural features, mechanism of action, therapeutic aim, advantages and limitations, chemical modification approaches and carrying strategies of AMPs. Finally, according to Quality by Design, the most important potential effective factor and potential risk were mentioned in the development of AMP delivery systems.

Antimicrobial resistance is one of the main global threats according to the World Health Organization's (WHO) report (World Health Organization 2014), therefore there is a need for the development of other agents, such as antimicrobial peptides (AMPs). Although AMPs are considered as major candidates for next-generation antibiotics, several challenges including low bioavailability, high manufacturing cost and toxicity are still to be solved for their practical use in therapeutic applications. Novel chemical modification approaches as well as strategies for their delivery offer several opportunities to overcome these barriers and develop more stable and cost-effective synthetic peptides with efficient delivery to the target site. The integration of the Quality by Design (QbD) approach in the early pharmaceutical developments supports researchers in optimizing the targeted product by a risk based manner. Peptide modifications and formulation of peptide delivery systems are challenging tasks and hide several risks. Understanding and evaluating the cause - effect relations within the initial Risk Assessment (RA) step in case of all attributes give the basis for the experimental design as the next step, and aids the formulation development in order to get the final product in the targeted quality range. This study presents a Quality by Design based antimicrobial peptide modification and formulation design. Analyses the potential risks in the AMP PEGylation process through the example of PGLa. The QbD based initial RA screened and evaluated the risk factors in this AMP modification procedure. The critical quality and process related factors were defined and their ranking was performed due to their estimated critical effect on the PEGylated AMP. This pre-formulation design study highlights the critical risk factors as decision points for the further steps.