Antimicrobial resistance has been a global health challenge that threatens our ability to control and treat life-threatening bacterial infections. Despite ongoing efforts to identify new drugs or alternatives to antibiotics, no new classes of antibiotic or their alternatives have been clinically approved in the last three decades. A combination of antibiotics and non-antibiotic compounds that could inhibit bacterial resistance determinants or enhance antibiotic activity offers a sustainable and effective strategy to confront multidrug-resistant bacteria. In this review, we provide a brief overview of the co-evolution of antibiotic discovery and the development of bacterial resistance. We summarize drug-drug interactions and uncover the art of repurposing non-antibiotic drugs as potential antibiotic adjuvants, including discussing classification and mechanisms of action, as well as reporting novel screening platforms. A pathogen-by-pathogen approach is then proposed to highlight the critical value of drug repurposing and its therapeutic potential. Finally, general advantages, challenges and development trends of drug combination strategy are discussed.

Drug repurposing for next-generation combination therapies against multidrug-resistant bacteria.

Plant growth-promoting bacteria (PGPB), possess multifarious beneficial traits and facilitate plant growth by both direct and indirect mechanisms under hostile conditions. The objective of the current study was to evaluate the potential application of 1-aminocyclopropane-1-carboxylate deaminase (ACC deaminase) producing plant-growth promoting endophyte bacterium (PGPEB) Kocuria rhizophila strain 14ASP (National Center for Biotechnology Information; NCBI) Accession Number: LFIY00000000.1) heavy metals and salt resistance tolerance under hostile environment. The in vitro study was conducted to evaluate plant growth promotion characteristics, heavy metal and salt resistance of the K. rhizophila under normal and stressful environments. The strain 14ASP revealed the plant-growth promoting and of AAC deaminase activities under abiotic stress environment. K. rhizophila showed significant tolerance against different heavy metals on LB (Luria Ber-tani) agar plates and broth medium supplemented with cadmium (Cd), (50 mg L−1), cooper (Cu), (50 mg L−1), nickel (Ni), (50 mg L−1), lead (Pb), (200 mg L−1) and chromium (Cr) (500 mg L−1), respectively. It also exhibited population density (OD = 0.31–0.45) at different concentrations of sodium chloride (NaCl) (0% 5%, 10%, and 15% w/v) in LB medium. The draft genome of strain 14ASP is 2.6 Mb and was assembled into 183 contigs with 2689,1 bp and a G + C content of 70% and 1,882,646 bp, encoded 2409 protein, 8 rRNAs and 46 tRNAs. Genome analysis identified genes, involved in hydrocarbon metabolism, heavy metal tolerance, biofilm formation, Indole Acetic Acid (IAA) and siderophore biosynthesis. All these properties were confirmed by in silico and draft genome analysis.

Biotechnological approaches in agriculture and environmental management - bacterium Kocuria rhizophila 14ASP as heavy metal and salt- tolerant plant growth- promoting strain

There is an urgent need for new therapies to overcome antimicrobial resistance (AMR) especially against Gram-negative bacilli (GNB). Multicomponent therapy combining antibiotics with enhancer molecules known as adjuvants is an emerging strategy to combat AMR. We have previously reported tobramycin-based adjuvants which are able to potentiate various antibiotics. In order to expand the repertoire of tobramycin hybrid adjuvants, a new hybrid containing niclosamide, an FDA approved anthelmintic which has recently demonstrated a variety of interesting biological effects, was synthesized. It was found that this conjugate can potentiate several antibiotics against multidrug-resistant GNB, including the recently approved siderophore cephalosporin cefiderocol. 8 μg ml-1 of the niclosamide-tobramycin hybrid in combination therapy against a pandrug-resistant strain of P. aeruginosa was able to lower the cefiderocol MIC 32-fold, from 8 μg ml-1 to 0.25 μg ml-1 in iron-rich media where siderophore uptake is reduced. These results indicate that a niclosamide-tobramycin hybrid adjuvant can serve to potentiate a newly approved antibiotic.

A niclosamide–tobramycin hybrid adjuvant potentiates cefiderocol against P. aeruginosa

Bacterial infections are among the leading causes of death worldwide. The emergence of antimicrobial resistance factors threatens the efficacy of all current antimicrobial agents, with some already made ineffective, and, as a result, there is an urgent need for new treatment approaches. International organizations such as the World Health Organization and the European Centre for Diseases Control have recognized infections caused by multi-drug-resistant (MDR) bacteria as a priority for global health action. Classical antimicrobial drug discovery involves in vitro screening for antimicrobial candidates, Structure Activity Relationship analysis, followed by in vivo testing for toxicity. Bringing drugs from the bench to the bedside involves huge expenditures in time and resources. This, along with the relatively short window of therapeutic application for antibiotics attributed to the rapid emergence of drug resistance, has, at least until recently, resulted in a waning interest in antibiotic discovery among pharmaceutical companies. In this environment, "repurposing" (defined as investigating new uses for existing approved drugs) has gained renewed interest, as reflected by several recent studies, and may help to speed up the drug development process and save years of expensive research invested in antimicrobial drug development. The goal of this review is to provide an overview of the scientific evidence on potential anthelmintic drugs targeting Gram-negative bacilli (GNB). In particular, we aim to: (i) highlight the potential of anthelmintic drugs for treatments of GNB infections; (ii) review their mechanisms of action against these bacteria; (iii) summarize the outcome of preclinical studies investigating approved anthelmintic drugs that target these bacteria; (iv) provide critical challenges for further anthelmintic repurposing drugs development; and (v) list the Specific anthelmintic drugs that may be more likely to be repurposed.

Gregory Jackson

Papers

Overcoming β-Lactam resistance in Pseudomonas aeruginosa using non-canonical tobramycin-based antibiotic adjuvants

A niclosamide–tobramycin hybrid adjuvant potentiates cefiderocol against P. aeruginosa