pathogens Review Current State and Promising Opportunities on Pharmaceutical Approaches in the Treatment of Polymicrobial Diseases Sartini Sartini 1 , Andi Dian Permana 1 , Saikat Mitra 2 , Abu Montakim Tareq 3 , Emil Salim 4 , Islamudin Ahmad 5 , Harapan Harapan 6,7,8 , Talha Bin Emran 9 and Firzan Nainu 1, *   Citation: Sartini, S.; Permana, A.D.; Mitra, S.; Tareq, A.M.; Salim, E.; Ahmad, I.; Harapan, H.; Emran, T.B.; Nainu, F. Current State and Promising Opportunities on Pharmaceutical Approaches in the Treatment of Polymicrobial Diseases. Pathogens 2021, 10, 245. https://doi.org/10.3390/ pathogens10020245 Academic Editor: Catherine Wakeman Received: 10 January 2021 Accepted: 18 February 2021 Published: 20 February 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia; sardj@farmasi.unhas.ac.id (S.S.); andi.dian.permana@farmasi.unhas.ac.id (A.D.P.) 2 Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka 1000, Bangladesh; saikatmitradu@gmail.com or saikat-2018926336@pharmacy.du.ac.bd 3 Department of Pharmacy, International Islamic University Chittagong, Chittagong 4318, Bangladesh; montakim0.abu@gmail.com or abu.muntakim@dblab.org 4 Faculty of Pharmacy, Universitas Sumatera Utara, North Sumatera 20155, Indonesia; emilsalim@usu.ac.id 5 Faculty of Pharmacy, Universitas Mulawarman, East Kalimantan 75119, Indonesia; islamudinahmad@farmasi.unmul.ac.id 6 Medical Research Unit, School of Medicine, Universitas Syiah Kuala, Banda Aceh 23111, Indonesia; harapan@unsyiah.ac.id 7 Tropical Disease Centre, School of Medicine, Universitas Syiah Kuala, Banda Aceh 23111, Indonesia 8 Department of Microbiology, School of Medicine, Universitas Syiah Kuala, Banda Aceh 23111, Indonesia 9 Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh; talhabmb@bgctub.ac.bd * Correspondence: firzannainu@unhas.ac.id; Tel.: +62-821-9131-0384 Abstract: In recent years, the emergence of newly identified acute and chronic infectious disorders caused by diverse combinations of pathogens, termed polymicrobial diseases, has had catastrophic consequences for humans. Antimicrobial agents have been clinically proven to be effective in the pharmacological treatment of polymicrobial diseases. Unfortunately, an increasing trend in the emergence of multi-drug-resistant pathogens and limited options for delivery of antimicrobial drugs might seriously impact humans’ efforts to combat polymicrobial diseases in the coming decades. New antimicrobial agents with novel mechanism(s) of action and new pharmaceutical formulations or delivery systems to target infected sites are urgently required. In this review, we discuss the prospective use of novel antimicrobial compounds isolated from natural products to treat polymicrobial infections, mainly via mechanisms related to inhibition of biofilm formation. Drug-delivery systems developed to deliver antimicrobial compounds to both intracellular and extracellular pathogens are discussed. We further discuss the effectiveness of several biofilm-targeted delivery strategies to eliminate polymicrobial biofilms. At the end, we review the applications and promising opportunities for various drug-delivery systems, when compared to conventional antimicrobial therapy, as a pharmacological means to treat polymicrobial diseases. Keywords: polymicrobial diseases; biofilms; antimicrobials; natural products; pharmacological approach; drug delivery system 1. Introduction Microorganisms commonly grow in multifaceted polymicrobial biofilm communities in nature, attached to host mucosal sites and environmental surfaces [1]. By definition, polymicrobial biofilm communities comprise multiple microbial organisms (fungi, bacteria, and viruses) inhabiting a matrix that consists of microbes’ metabolic products and/or host- derived components, usually in the form of polysaccharides [1]. Polymicrobial communities exist in the human oral cavity, nasal cavity, gastrointestinal (GI) tract, respiratory tract, and urogenital tract [2]. Pathogens 2021, 10, 245. https://doi.org/10.3390/pathogens10020245 https://www.mdpi.com/journal/pathogens