Complementary supramolecular drug associates in perfecting the multidrug therapy against multidrug resistant bacteria

Abstract

The inappropriate and inconsistent use of antibiotics in combating multidrug-resistant bacteria exacerbates their drug resistance through a few distinct pathways. Firstly, these bacteria can accumulate multiple genes, each conferring resistance to a specific drug, within a single cell. This accumulation usually takes place on resistance plasmids (R). Secondly, multidrug resistance can arise from the heightened expression of genes encoding multidrug efflux pumps, which expel a broad spectrum of drugs from the bacterial cells. Additionally, bacteria can also eliminate or destroy antibiotic molecules by modifying enzymes or cell walls and removing porins. A significant limitation of traditional multidrug therapy lies in its inability to guarantee the simultaneous delivery of various drug molecules to a specific bacterial cell, thereby fostering incremental drug resistance in either of these paths. Consequently, this approach prolongs the treatment duration. Rather than using a biologically unimportant coformer in forming cocrystals, another drug molecule can be selected either for protecting another drug molecule or, can be selected for its complementary activities to kill a bacteria cell synergistically. The development of a multidrug cocrystal not only improves tabletability and plasticity but also enables the simultaneous delivery of multiple drugs to a specific bacterial cell, philosophically perfecting multidrug therapy. By adhering to the fundamental tenets of multidrug therapy, the synergistic effects of these drug molecules can effectively eradicate bacteria, even before they have the chance to develop resistance. This approach has the potential to shorten treatment periods, reduce costs, and mitigate drug resistance. Herein, four hypotheses are presented to create complementary drug cocrystals capable of simultaneously reaching bacterial cells, effectively destroying them before multidrug resistance can develop. The ongoing surge in the development of novel drugs provides another opportunity in the fight against bacteria that are constantly gaining resistance to existing treatments. This endeavour holds the potential to combat a wide array of multidrug-resistant bacteria.

Keywords: binary antibiotic systems; cell membrane permeability; complementary drugs; complementary multidrug cocrystal; crystal engineering; efflux pump; supramolecular synthon.

Scheme 1

A schematic presentation depicts how multidrug therapy can be improved. The complementary tuberculosis drugs with the potentiality of forming carboxylic acid–carboxamide synthon may form cocrystals in certain solutions and possibly can be codelivered to treat tuberculosis.

Figure 1

Various first- and second-line tuberculosis drugs are presented.

Figure 2

Schematically conjugational transfer of the F plasmid from the donor to the recipient cell is represented here. The backbone of the F plasmid consists of various components: the tra regions, encompassing all genes responsible for conjugational transfer (depicted in light blue); the origin of transfer (oriT) highlighted in red; the leading region (depicted in green), which is the initial segment transferred into the recipient cell; and the maintenance region (depicted in dark blue), playing a role in plasmid replication and partition. (i) The conjugation gets started by the expression of the tra gene. Certain Tra proteins are responsible for assembling both the T4SS and the conjugative pilus. These structures play a pivotal role in attracting recipient cells and facilitating the stabilization of mating pairs during the process of conjugation. (ii) Additional Tra proteins, namely TraI, TraM, and TraY, make up the relaxosome complex. Working in tandem with the integration host factor (IHF), they specifically bind to the oriT site on the plasmid. Their role is crucial in preparing the plasmid for transfer by initiating the nicking reaction through the TraI relaxase enzyme. (iii) The transfer of the T-strand through the T4SS is triggered by the interaction between the Type IV Coupling Protein (T4CP) and Relaxosome. This interaction marks the initiation point for the transfer process. (iv, v) As the TraI-bound T-strand moves to the recipient, the donor undergoes Rolling Circle Replication (RCR), converting single-stranded DNA (ssDNA) into double-stranded DNA (dsDNA) concurrently. (A) Upon entering the recipient, the single-stranded DNA (ssDNA) T-strand becomes enveloped by the host chromosomal SSB. Simultaneously, the single-stranded promoter Frpo takes on a stem-loop structure that the host RNA polymerase identifies to kickstart RNA primer synthesis. (B) TraI facilitates the circularization process of the completely internalized T-strand. (C) The host DNA polymerase identifies the RNA-DNA duplex, triggering the initiation of the complementary strand synthesis. (D) Upon completion of the conversion from ssDNA to dsDNA within the plasmid, the expression of plasmid genes triggers a phenotypic transformation in the recipient cell, turning it into a transconjugant cell. (Ref 3).

Figure 3

Five major families of efflux pumps are schematically presented here. (i) resistance-nodulation-division (RND), (ii) small multidrug resistance (SMR), (iii) major facilitator superfamily (MFS), (iv) multidrug and toxic compound extrusion (MATE), and (v) ATP-binding cassette (ABC) superfamily. The abbreviations used in this context expand as follows: OMP, Outer membrane protein; OM, Outer membrane; ATP, Adenosine triphosphate; ADP, Adenosine diphosphate; IM, Inner membrane.

Figure 4

The figure illustrates the cell membrane structures of Gram-positive and Gram-negative bacteria.

Figure 5

Several antibiotic resistance mechanisms in bacteria are presented here schematically. The left and right sides denote the presentation of Gram-positive and Gram-negative bacteria, respectively. Bacteria acquire enzymes that neutralize the drugs, efflux pumps actively move particular or multiple antibiotics out of the cell, alternative metabolic routes replace those blocked by the medication, the antibiotic’s target site undergoes modification, reducing the drug’s affinity to the binding sites, and decreased permeability results in reduced drug accumulation within the cell.

Figure 6

Different supramolecular synthons utilized in the development of drug-drug cocrystals can be found in the Cambridge Structure Database (CSD) (21).