The discovery of penicillin nearly 90 years ago revolutionized the treatment of bacterial disease. Since that time, numerous other antibiotics have been discovered from bacteria and fungi, or developed by chemical synthesis and have become effective chemotherapeutic options. However, the misuse of antibiotics has lessened the efficacy of many commonly used antibiotics. The emergence of resistant strains of bacteria has seriously limited our ability to treat bacterial illness, and new antibiotics are desperately needed. Since the discovery of penicillin, most antibiotic development has focused on the discovery of new antibiotics derived from microbial sources, or on the synthesis of new compounds using existing antibiotic scaffolds to the detriment of other lines of discovery. Both of these methods have been fruitful. However, for a number of reasons discussed in this review, these strategies are unlikely to provide the same wealth of new antibiotics in the future. Indeed, the number of newly developed antibiotics has decreased dramatically in recent years. Instead, a reexamination of traditional medicines has become more common and has already provided several new antibiotics. Traditional medicine plants are likely to provide further new antibiotics in the future. However, the use of plant extracts or pure natural compounds in combination with conventional antibiotics may hold greater promise for rapidly providing affordable treatment options. Indeed, some combinational antibiotic therapies are already clinically available. This study reviews the recent literature on combinational antibiotic therapies to highlight their potential and to guide future research in this field.

Pseudomonas aeruginosa (P. aeruginosa) poses a grave clinical challenge due to its multidrug resistance (MDR) phenotype, leading to severe and life-threatening infections. This bacterium exhibits both intrinsic resistance to various antipseudomonal agents and acquired resistance against nearly all available antibiotics, contributing to its MDR phenotype. Multiple mechanisms, including enzyme production, loss of outer membrane proteins, target mutations, and multidrug efflux systems, contribute to its antimicrobial resistance. The clinical importance of addressing MDR in P. aeruginosa is paramount, and one pivotal determinant is the resistance-nodulation-division (RND) family of drug/proton antiporters, notably the Mex efflux pumps. These pumps function as crucial defenders, reinforcing the emergence of extensively drug-resistant (XDR) and pandrug-resistant (PDR) strains, which underscores the urgency of the situation. Overcoming this challenge necessitates the exploration and development of potent efflux pump inhibitors (EPIs) to restore the efficacy of existing antipseudomonal drugs. By effectively countering or bypassing efflux activities, EPIs hold tremendous potential for restoring the antibacterial activity against P. aeruginosa and other Gram-negative pathogens. This review focuses on concurrent MDR, highlighting the clinical significance of efflux pumps, particularly the Mex efflux pumps, in driving MDR. It explores promising EPIs and delves into the structural characteristics of the MexB subunit and its substrate binding sites.

The development of multiple-drug-resistant pathogens has prompted medical research toward the development of new and effective antimicrobial therapies. Much research into novel antibiotics has focused on bacterial and fungal compounds, and on chemical modification of existing compounds to increase their efficacy or reactivate their antimicrobial properties. In contrast, cyanobacteria have been relatively overlooked for antibiotic discovery, and much more work is required. This may be because some cyanobacterial species produce environmental toxins, leading to concerns about the safety of cyanobacterial compounds in therapy. Despite this, several cyanobacterial-derived compounds have been identified with noteworthy inhibitory activity against bacterial, fungal and protozoal growth, as well as viral replication. Additionally, many of these compounds have relatively low toxicity and are therefore relevant targets for drug development. Of particular note, several linear and heterocyclic peptides and depsipeptides with potent activity and good safety indexes have been identified and are undergoing development as antimicrobial chemotherapies. However, substantial further studies are required to identify and screen the myriad other cyanobacterial-derived compounds to evaluate their therapeutic potential. This study reviews the known phytochemistry of cyanobacteria, and where relevant, the effects of those compounds against bacterial, fungal, protozoal and viral pathogens, with the aim of highlighting gaps in the literature and focusing future studies in this field.